HU208977B - Process for producing (1) benzopyrano [4,3-c] pyrazols and of medical preparatives containing them - Google Patents

Abstract

The invention relates to processes for the preparation of * the formula * in which R1 to R10 have the meaning given in the description, which are used as therapeutics because of their immunomodulatory effect. The compounds of the formula I are prepared by processes known per se. Formula (I) {* Pharmaceuticals; Effect, immunomodulatory}

Description

FIELD OF THE INVENTION The present invention relates to novel pharmaceutically active compounds, in particular [1] benzopyrano [4,3-c] pyrazoles of the formula I, and to pharmaceutical compositions containing them. The compounds of the present invention are immunomodulatory.

U.S. Patent No. 4,268,816 discloses certain compounds which are capable of suppressing the immune response in mammals. These compounds are 1,2,3,4-tetrahydro [1] benzothiopyrano [4,3-c] pyrazol-3-ones [see formula (A)] and 2,3-dihydro [1] benzothiopyrano Form a small group of [4,3-c] pyrazol-3-ones [see formula (B)] wherein n = 0, 1 or 2; R is phenyl, phenyl monosubstituted with chloro, bromo, fluoro, methyl, methoxy, nitro or trifluoromethyl, or phenyl disubstituted with chloro; and X is hydrogen or chlorine.

The present invention relates to the preparation of compounds of formula I; in the formula R! hydrogen or R _{2 is} bond,

R ₂ is a bond to one of R or R ₃ ,

R ₃ is a bond with one of R ₂ or R ₄ ,

R _{4 is} hydrogen or R _{3 is} bond,

R _{5 is} hydrogen or methyl,

R _{6 is} hydrogen, halogen, C 2 -C 6 alkanoyl, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, carbamoyl - or a carboxy group or a R ₅ and R ₆ carbon atom to which they are attached form a cyclopropyl group.

R _{7 is} hydrogen, halogen, trifluoromethyl, methoxy, C 1-6 alkyl, C 1-6 alkylthio or C 1-6 alkylsulfinyl,

R _{8 is} hydrogen, halogen or trifluoromethyl,

R ₉ and R _{10 are the} same or different halogen atoms or R _{9 is} hydrogen and R _{10 is} hydrogen, halogen, trifluoromethyl, hydroxy, nitro, C 2 -C 6 alkanoyloxy, C 1 -C 6 alkyl or C 1 -C 6 alkyl; -C alkoxy radical, with the proviso that if R) and R represent _two bonds, and R ₃ and R ₄ represent a bond and R _6, R _7, R ₈ and R ₁₀ are each hydrogen, R ₉ is hydrogen or 8-methyl , then R _{5 is} other than hydrogen.

The compounds of formula I have been found to possess immunomodulatory activity.

Tetrahedron Letters (1987, 28, No. 43, 5165-5168) discloses a compound of formula (I) wherein R 1 and R _{2 are a} bond, R ₃ and R _{4 are} also a bond, and R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are each hydrogen. However, no reference is made to the pharmaceutical activity of the compound in this reference.

Indian J. Chem. Sect. 24B (12), 1288-1290 (1985) discloses a compound of formula (I) wherein R _{9 is a} 8-methyl group, the other substituents being as set forth in the above publication.

It should be noted that groups containing three or more carbon atoms in the compounds may be straight or branched. For example, propyl includes n-propyl and isopropyl, and butyl includes η-butyl, sec-butyl, isobutyl and tert-butyl. The term "halogen" refers to a fluorine, chlorine or bromine atom.

A preferred group of compounds of formula (I) are those compounds wherein R 1 and R _{2 are taken} together to form a bond and R ₃ and R ₄ are also taken together, i.e., compounds of formula (II). R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R _{10 are as} defined in formula (I).

A further preferred class of compounds of formula (I) are those compounds that represent a bond and R ₄ is hydrogen, i.e. the compounds and their tautomers of formula (III) R, is hydrogen, R ₂ and R ₃ together atom. R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R _{10 are as} defined in formula (I).

The compounds of formula (I) where _R5 is methyl, then R ₆ is preferably other than hydrogen, for example C 1-6 alkoxycarbonyl. The preferred compound (I) of the formula R ₅ is hydrogen or R ₆ groups and the atom to which they are attached represent a cyclopropyl group. More preferably, R _{5 is} hydrogen.

Preferably R ₆ is hydrogen, halogen, C 2 -C 4 alanyl such as acetyl, ethanol or propanoyl, C 2 -C 6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl. C 1-4 alkylthio such as methylthio, ethylthio or propylthio, C 1-4 alkylsulfinyl such as methylsulfinyl, ethylsulfinyl or propylsulfonyl, C 1-4 alkylsulfonyl, for example, methylsulfonyl, ethylsulfonyl, or propylsulfonyl, carbamoyl or carboxy; or R _h R which they are attached represent a cyclopropyl group and the ₅ carbon atom. In another group of compounds, R _{6 is} hydrogen, C 2 -C 6 alkoxycarbonyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, carbamoyl or carboxy, or R ₆ R ₅ represents a cyclopropyl group and the carbon to which they are attached, but especially hydrogen or 2-6C-alkoxycarbonyl, _R6 is most preferably hydrogen, chlorine or bromine atom, acetyl, C2-4 alkoxycarbonyl, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, carbamoyl or carboxy; or R ₆ with R ₅ and the carbon atom to which they are attached are cyclopropyl. Particularly preferred are compounds in which R ₆ is hydrogen, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or methylthio, especially hydrogen or C2-4 alkoxycarbonyl, such as propoxycarbonyl, i.e. n -propoxycarbonyl or isopropoxycarbonyl.

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Suitably R ₇ is hydrogen, halogen, trifluoromethyl, C 1-6 alkyl, preferably

C 1-4 alkyl such as methyl, ethyl or propyl; C 1-6 alkylthio such as methylthio or ethylthio; or C 1-6 alkylsulfinyl such as methylsulfinyl or ethylsulfonyl. In preferred compounds of formula I, R _{7 is} hydrogen, fluoro or chloro, trifluoromethyl, C 1-6 alkylthio, or C 1-6 alkylsulfinyl. More preferably, R ₇ is hydrogen, fluoro, chloro, trifluoromethyl, C 1-4 alkylthio, or C 1-4 alkylsulfinyl. _R7 is most preferably hydrogen, fluoro, chloro, trifluoromethyl, methylthio or methyl sulfinyl.

Particularly preferred are compounds of formula (I), wherein R ₇ fluorine, chlorine, trifluoromethyl or methylthio, more preferably fluoro, chloro or trifluoromethyl, especially fluoro or chloro.

In the preferred compounds of formula I, R _{8 is} hydrogen, fluoro or chloro, more preferably hydrogen or chloro, most preferably hydrogen.

The substituents R c) and R ₁₀ may be in any position on the benzene ring, i.e., 6-, 7-, 8- and / or

9- position. Accordingly, each of said R ₉ and R ₁₀ substituents may occupy any position.

In preferred compounds of formula I, R ₉ is hydrogen.

Preferably R ₁₀ is hydrogen, fluoro, trifluoromethyl, hydroxy, nitro, C 2 -C 6 alkanoyloxy (especially in the 8- or 9-position of the benzene ring) C 1 -C 6 alkyl (especially in the benzene ring of 8 or at the 9-position) or C 1-6 -alkoxy (especially at the 9-position of the benzene ring). As mentioned above, the R ₁₀ group may be in the 6-position, particularly as a 6-fluoro, 6-hydroxy or 6-methoxy substituent. The 7-position may also have a substituent such as 7-fluoro or 7-hydroxy. In preferred compounds of formula I, R _{10 is in} the 8- or 9-position of the benzene ring and is hydrogen, fluoro, trifluoromethyl, hydroxy, nitro, C 2 -C 6 alkanoyloxy such as acetoxy. a propionyloxy, butanoyloxy, or pentanoyloxy group; or a C1-C4 alkyl group such as methyl, ethyl or propyl. Preferably R _{10 is} also C 1-6 alkoxy such as methoxy, ethoxy, propoxy or butoxy at the 9-position of the benzene ring, more preferably C 1-4 alkoxy. _R10 is even more preferably hydrogen, fluoro, hydroxy or nitro and is preferably a C2-6 alkanoyloxy group also. R _l0 most preferably hydrogen, fluoro, hydroxy,

C2-C4 alkanoyloxy; or R _{10 is C} 1-4 alkoxy at the 9-position of the benzene ring. In particularly preferred compounds, R ₁₀ is hydrogen, fluoro, or C 2 -C 4 alkanoyloxy at the 8-position of the benzene ring, or hydroxy or C 1 -C 4 alkoxy at the 9-position of the benzene ring, such as 9-ethoxy. Particularly preferred compounds are those wherein R _{10 is} hydrogen or 8-fluoro.

A preferred group of compounds of the invention are those compounds wherein R _is hydrogen or a bond together with R _2; R ₂ represents a bond to one of R or R ₃ ; R ₃ is a bond to one of R ₂ or R ₄ ; R _{4 is} hydrogen or R _{3 is} bond; R _{5 is} hydrogen; R _{6 is} hydrogen, halogen, C 2 -C 6 alkanoyl, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, carbamoyl - either a carboxy group or R ₆ with R ₅ and the carbon atom to which they are attached are cyclopropyl; R _{7 is} hydrogen, fluoro, chloro, trifluoromethyl, C 1-6 alkylthio or C 1-6 alkylsulfinyl; R _{8 is} hydrogen or chloro; and R ₉ and R ₁₀ are each fluoro or R _{9 is} hydrogen and R _{10 is} substituted at the 8- or 9-position of the benzene ring and is hydrogen, fluoro, trifluoromethyl, hydroxy, nitro, C 2 -C 6 alkanoyloxy; or C 1-6 alkyl or R _{10 C} 1-6 alkoxy at the 9-position of the benzene ring.

An even more preferred group of compounds of formula I are those wherein R _{b is} R ₂ , R ₃ , R ₄ , R ₅ , R ₇ , R ₈ and R ₉ as described in the preceding paragraph; R _{6 is} hydrogen, (C 2 -C 6) alkoxycarbonyl, (C 1 -C 6) alkylsulfinyl, (C 1 -C 6) alkylsulfonyl, carbamoyl or carboxy, or R _{6 is taken together} with R ₅ and the carbon atom to which they are attached to form cyclopropyl; and R ₁₀ is at the 8 or 9 position of the benzene ring and is hydrogen, fluoro, trifluoromethyl, hydroxy, nitro or C 1-6 alkyl or R _{10 is} C 1-6 alkoxy at the 9 position of the ring system .

In the compounds of formula (II), the substituents R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ may be as defined above. In a preferred group of compounds of formula II, R _{5 is} hydrogen, R _{6 is} hydrogen, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl or methylthio, R _{7 is} fluoro, chloro or bromine, trifluoromethyl or methylthio, especially fluorine, chlorine or trifluoromethyl, R ₈ hydrogen or chlorine, R ₉ hydrogen and R ₁₀ hydrogen, 9-hydroxy, 9-ethoxy, 8-propionyloxy or 8-fluoro .

In the compounds of formula (III), the substituents R ₅ , R ₆ , ^R 7> ^R 8 ' ^R 9 and R ₁₀ may be as defined above. The compounds of formula (III), a preferred group R ₅ and R ₆ are each hydrogen, _R7 is hydrogen or chlorine, R ₈ is hydrogen or chlorine and R ₉ and R ₁₀ are each hydrogen.

The compounds of formula (I) may have one or more chiral centers and may exist in various optically active forms. If (I) is general

Since the compounds of the formula have a chiral center, the compounds exist in two enantiomeric forms. The present invention includes the preparation of both enantiomers and mixtures of enantiomers. Enantiomers may be resolved by methods known to those skilled in the art, such as high performance liquid chromatography on a chiral support such as silica gel coupled to a chiral ligand.

For example, the following compounds of formula (I) may be present as the (R) - and (S) -enantiomers: Ethyl [2- (4-chlorophenyl) -? - methyl-3-oxo-2,3-dihydro [ l] benzopyrano [4,3-c] pyrazole-4-acetate] 2- (4-chlorophenyl) -4-methylsulfinylmethyl- [1] benzopyrano [4,3-c] pyrazole; 3 (2H) -one

4-Methyl-2- (4-trifluoromethyl-phenyl) -1,4-dihydro- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 2- (3-chloro-phenyl) -4 methyl-l, 4-dihydro- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one

2- (3,4-dichlorophenyl) -4-methyl-l, 4-dihydro- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one

2- (4-chlorophenyl) -4-methyl-l, 4-dihydro- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one

2- (4-fluorophenyl) -4-methyl-l, 4-dihydro- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one

When the compounds of formula I contain more than one chiral center, the compounds may exist in diastereoisomeric forms. The present invention relates to the preparation of mixtures of each of the diastereoisomers and diastereoisomers. The diastereoisomers may be separated by methods known to those skilled in the art, such as crystallization and subsequent resolution.

The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I in pharmaceutically acceptable diluents or carriers.

For therapeutic use, the active ingredient may be administered orally, rectally, parenterally or topically, preferably orally or topically. Thus, the pharmaceutical compositions of the present invention may be in the form of any known pharmaceutical composition for oral, rectal, parenteral or topical application. Suitable pharmaceutically acceptable excipients for use in such formulations are well known in the pharmaceutical art. The compositions of the present invention may contain from 0.9% to 90% by weight of the active ingredient. The compositions are generally formulated in a unit dosage form. Binders used in the preparation of formulations are those known in the pharmaceutical art.

Compositions for oral administration are preferred compositions of the present invention and are available in known pharmaceutical forms suitable for such administration, such as tablets, capsules, syrups and aqueous or oily suspensions.

Tablets may be prepared by mixing the active ingredient with an inert diluent such as calcium phosphate in the presence of disintegrating agents such as corn starch and lubricating agents such as magnesium stearate, and preparing the mixture in the known manner. Tablets may be formulated in a manner known to those skilled in the art to provide delayed release of the active compounds of the invention. If desired, such tablets may be enteric-coated, for example using cellulose acetate phthalate, in known manner.

Likewise, capsules, for example hard or soft gelatin capsules, which may contain the active ingredient with or without a binder, and if desired enterally coated, may be prepared by known methods. Each tablet and capsule preferably contains from 0.1 to 500 mg of active ingredient. Other formulations suitable for oral administration include aqueous suspensions containing the active ingredient in an aqueous medium in the presence of a nontoxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions which form a compound of the invention in a suitable vegetable oil, e.g. arachis oil.

Topical formulations are also preferred compositions of the invention. The pharmaceutically active compounds may be formulated in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be formulated by dispersing the active ingredient in an aqueous medium using a surfactant mixed with a topical excipient such as petrolatum and / or light liquid paraffin. An ointment may be formulated by admixing the active ingredient with a topical excipient such as mineral oil, petrolatum and / or wax, such as paraffin wax or beeswax. Gels may be prepared by admixing the active ingredient with a gelling agent such as Carbomer BP, for topical application in the presence of water. The topical formulations may further comprise a matrix in which the therapeutically active compound of the present invention is dispersed so that the compounds can be used as transdermal compounds upon contact with the skin. Suitable transdermal formulations may be prepared by admixing the therapeutic agent with a suitable excipient such as those mentioned above for topical administration, together with a potential transdermal accelerator such as dimethylsulfoxide or propylene glycol.

Formulations according to the invention suitable for rectal administration are known pharmaceutical forms for administration such as cocoa butter or polyethylene glycol based suppositories.

Formulations suitable for parenteral administration may be formulated according to known art forms such as sterile suspensions or sterile solutions in a suitable solvent.

In some formulations it may be useful to use the compounds of the invention in the form of very small particles, such as those produced by fluid energy.

In the compositions of the present invention, the active ingredient may optionally be mixed with other compatible therapeutically effective components.

The compounds of formula I are immunomodulatory

They are immunosuppressive agents, but some compounds may also exhibit immunostimulatory effects in certain disease states. The compounds of the present invention are useful in the treatment of diseases resulting from aberrant immune reactions. Thus, pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) are useful in the treatment of diseases related to immunology, such as the ejection of tissues such as kidneys; autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus; skin disorders such as contact sensitivity and psoriasis; and neoplasia such as melanoma.

In these treatments, the daily amount of the compounds of the formula I administered is a therapeutically effective amount, generally 0.1 to 2000 mg, preferably 1500 mg.

The present invention relates to a method for treating diseases related to immunology by administering to a patient a therapeutically effective amount of a compound of formula (I).

The following describes methods for preparing the compounds of formula (I).

Compounds of formula (I) represented by formula (II) may be prepared by oxidation of compounds of formula (I) represented by formula (III), for example by reaction with chloranil.

Compounds of formula (I) represented by formula (II) may also be prepared by reacting a compound of formula (IV) or a tautomer thereof with an orthoester of formula (Va) or a thio-ester of formula (Vb) C 1-4 -C 4 alkyl or benzyl, for example by heating at 50-200 ° C.

Compounds of formula (I) represented by formula (II) wherein R _{6 is C} 2-6 alkanoyl may be prepared by reacting a compound of formula (IV) with 2,2,6-tri (C 1-6 alkyl) For example, the reaction with -4 H -1,3-dioxo-5-en-4-one (wherein the C 1 -C 6 alkyl groups may be the same or different) is carried out at 50-200 ° C in an organic liquid.

Compounds of formula (I) represented by formula (II) may be prepared by reacting a compound of formula (VI) wherein R _{n is} hydrogen, or a tautomer thereof, or wherein R _n is -COR ₁₃ . wherein R _{13 is} hydrogen, benzyl or C 1 -C 4 alkyl, and R ₁₂ is -COCHR ₅ R ₆ , with a base such as piperidine in a suitable solvent such as ethanol.

Compounds of formula (I) represented by formula (III) may be prepared by reduction of a compound of formula (I) represented by formula (II), for example, with sodium borohydride.

Compounds of formula (I) represented by formula (III) are prepared by reacting a compound of formula (VII) wherein R _{14 is C} 1 -C 4 alkyl or benzyl with a compound of formula VIII such as 50-200 ° C in an organic liquid such as toluene.

Compounds of formula (IV) are prepared by reacting a compound of formula (IX) with a compound of formula (VIII), such as 50200C, in an organic liquid such as toluene. Preferably, the compound of formula VIII is used in excess of the stoichiometric amount.

The compounds of formula (IV) may also be prepared by reacting a compound of formula (X) with an acid such as hydrochloric acid or a base such as sodium hydroxide solution.

Compounds of formula Va are prepared by reacting a compound of formula R ₅ R ₆ CHCN with an alcohol YOH in the presence of anhydrous acid such as hydrochloric acid. Thus, R ₅ R ₆ CHC (= NH) OY are obtained as acid salts, for example hydrochloride salts, which are then reacted with additional alcohol YOH.

The compounds of formula (Vb) can be prepared, for example, is reacted with a R ₅ R ₆ CHCOC1 compound Lewis acid such as zinc chloride in the presence of a thiol of formula YSH.

Compounds of formula (VI) wherein R _n is -COR ₁₃ and R ₁₂ is -COCHR ₆ R ₅ are prepared by reacting a compound of formula (VI) wherein R A -COR, a group of formula ₃ , and R _{12 are} hydrogen atoms are reacted with an acid halide such as an acid chloride of formula R ₅ R ₆ COCl.

Compounds of formula (VI) wherein Rh is -COR _{) 3} and R ₁ is hydrogen. ₂ H, is prepared by reacting a compound of formula IV with, for example, an acid anhydride of formula R ₁₃ CO) ₂ O in the presence of a corresponding acid salt such as sodium.

Compounds of formula (VI), wherein R _u and R ₁₂ are identical and each is R ₅ R ₆ CO- may be prepared by reaction with a acylating a compound of formula (IV), for example a (R ₅ R ₆ CHCO) ₂ Using an acid anhydride of formula O in the presence of a salt of the corresponding acid.

Compounds of formula (VI) wherein R _{2 is} a -COCHR ₆ R ₅ group and R 1 are hydrogen or tautomers thereof are prepared by reacting a compound of formula (VI) wherein R a -COR ₁₃ radical and R an _I2 -COCHR ₅ R ₆ group in a suitable solvent such as ethanol, with a base such as piperidine is reacted.

Compounds of formula (VII) are prepared by alkylating or cycloalkylating a compound of formula (XI), for example, by reacting the compound with lithium dialkyl copper.

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Compounds of formula (VIII) may be prepared by methods known to those skilled in the art.

Compounds of formula IX are prepared by reacting a compound of formula XII, wherein R _{15 is} hydrogen, with malonic acid in the presence of an acid chloride such as phosphoryl chloride and a Lewis acid such as zinc chloride.

Compounds of formula IX may also be prepared by reacting a compound of formula XII, wherein R _{15 is} an acetyl group, with a dialkyl carbonate of formula (YO) ₂ CO in the presence of a base such as sodium hydride, Or a benzyl group such as dimethyl carbonate.

Compounds of formula (X) are prepared by reacting a compound of formula (IX) with a hydrazine of formula (VIII), for example 50-200 'Con, in a suitable solvent such as toluene. In cases where mixtures of compounds of formula (IV) and (X) are obtained, these compounds may be separated on the basis of their different solubilities in an organic liquid such as dichloromethane.

Compounds of formula XI may be prepared by methods known to those skilled in the art.

Compounds of formula XII may be prepared by methods known to those skilled in the art.

Compounds of formula (II) wherein R _{10 is} hydroxy may be prepared by reacting a compound of formula (II) wherein R _{10 is C} 1-6 alkoxy with a Lewis acid such as aluminum chloride. Compounds of formula II wherein R _{10 is C} 2 -C 6 alkoxycarbonyl are prepared by acylation of a compound of formula II wherein R _{10 is} hydroxy, for example with the corresponding acid halide. Compounds of formula (Π), wherein _R5 and _R6 are hydrogen are prepared by reacting a compound (II) of formula wherein R ₅ is hydrogen and R ₆ COOH, decarboxylation; or a compound of formula II wherein R _{6 is} hydrolyzable to a carboxyl group such as a C 2 -C 6 alkoxycarbonyl or carbamoyl group, for example by reaction with sulfuric acid and then decarboxylated. Compounds of formula II wherein R _{6 is C} 1-6 alkylsulfinyl or C 1-6 alkylsulfonyl are prepared by reacting a compound of formula II wherein R ₆ 1-6 alkylthio group such as 3-chloroperoxybenzoic acid.

Compounds of formula (IV) may be prepared by reacting a compound of formula (XIII) wherein R _{19 is a} carbamoyl group with a compound of formula (VIII).

Compounds of formula (XIII) wherein _R19 is carbamoyl may be prepared by reacting a formula (XIII), R ₉ represents cyano for example methanol saturated with hydrogen chloride and water is reacted with wherein.

Compounds of formula (XIII) wherein _{R19 is} cyano are prepared by reacting a compound of formula (XIV) with a base such as sodium ethoxide.

Compounds of formula (XIV) are prepared by reacting a compound of formula (XV) with hydroxylamine hydrochloride.

Compounds of formula XV are prepared from compounds of formula XIII wherein R _{9 is} hydrogen by heating the compound with, for example, ethyl formate in the presence of a base such as sodium ethoxide.

Some (I) compounds, such as those in which _R5 and _R6 are hydrogen, such as 2- (4-chlorophenyl) -4-methyl [l] benzopyrano [4,3-c] pyrazol-3 (2H ), 2- (4-fluorophenyl) -4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, or 2- (3,4-dichlorophenyl) -, The 4-methyl- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one can be rearranged in the presence of aqueous alkali and an organic liquid such as an alkanol such as isopropanol to give the dimer compounds of formula XVI.

The dimers formed in the above three cases are:

l- (4-chlorophenyl) -4- {l- [2- (4-chlorophenyl) -3-hydroxy-2,4-dihydro [l] benzopyrano [4,3-c] pyrazol-4-ylidene methyl] ethylidene} -3- (2-hydroxyphenyl) -2-pyrazolin-5-one. l- (4-fluorophenyl) -4- {l- [2- (4-fluorophenyl) -3-hydroxy-2,4-dihydro [l] benzopyrano [4,3-c] pyrazol-4-ylidene methyl] ethylidene} -3- (2-hydroxyphenyl) -2-pyrazon-5-one.

- (3,4-Dichlorophenyl) -4- {1- [2- (3,4-dichlorophenyl) -3-hydroxy-2,4-dihydro [1] benzopyrano [4,3-c] pyrazole 4-ylidenemethyl] ethylidene} -3- (2-hydroxyphenyl) -2-pyrazolin-5-one.

Certain intermediates of formula (II), (III), (IV), (V), (VI), (VII), (IX), (X), (XIII), (XIV) and (XV) are novel compounds.

The compounds of formula (I) prepared by the above procedures may be subjected to the following further operations:

(i) optionally (I) a compound of formula wherein R, _pp 1-6 alkoxy, dealkylating (I) a compound of formula wherein R ₁₀ is hydroxy, (ii) if desired (I) of formula acylating a compound of formula I wherein R _{10 is} hydroxy to form a compound of formula I wherein R _{10 is C} 2-6 alkanoyloxy; (iii) optionally, a compound of formula I wherein R ₆ and / or R _{C 7} -C 6 alkylthio, is oxidized to a compound of formula I wherein R ₆ and / or R _{7 is C} 1-6 alkylsulfinyl; (iv) optionally, a compound of formula I wherein R _{6 is a C} 1-6 alkylsulfinyl group oxidized to a compound of formula I wherein R _{6 is a C} 1-6 alkylsulfonyl group.

(v) optionally, a ve6 of formula (I)

The carbamoyl group is converted by hydrolysis followed by decarboxylation to a compound of formula I wherein R g is hydrogen, (vi) if desired, a compound of formula I wherein R _{6 is} C 2-6 alkoxy; -carbonyl group, is hydrolyzed to a compound of formula I wherein R _{6 is a} carboxy group.

The therapeutic effect of the compounds of the present invention was confirmed by the cutaneous hypersensitivity test (CH test) in which the compounds were administered parenterally to BALB / c mice. We performed this test as follows:

Female BALB / c mice weighing 16-24 g were used in a group of eight. The abdomen of each mouse was shaved and the shaved area treated with 20 μΐ 5% w / v (1: 1 acetone / ethanol) 4-ethoxymethylene-2-phenyloxazolin-5-one (oxazolone). Immediately after sensitization, the test compound was administered as a 1.5 volume% suspension of sorbitan ester (Tween 80) in 100 μΐ sterile water at one of the doses listed below, to the mice by intraperitoneal injection. 100 μΐ of the above suspension was similarly injected into the mice every 24 hours for a further seven days. The dosages chosen were 50, 30, 10, 3,1,0,3, 0,1, 0,03 and 0,01 mg / kg.

Two groups of eight to eight BABLB / c mice were used as controls in each assay, as described above, except that the test compound was not injected daily.

On the seventh day after sensitization, 10 μΐ of a 1% w / v solution of oxazolone (1: 1 or 1: 3 by volume in acetone / olive oil) was administered to one ear of each experimental mouse and control mice (this is the dose-induced ear). ). After 24 hours, the thickness of the treated ears of the mice and the untreated ears of the same animal were measured using an engineering screw micrometer. The difference in the thickness of the treated and untreated ears in each animal is the extent of the animal's response to oxazolone. Comparison between test compound treated mice and control mice indicates the efficacy of the test compound as an immunomodulatory agent. Compounds are believed to be effective at a given dose if there is a 20% or greater reduction in ear swelling, which is statistically significant (p <0.05) according to Dunnett's test - in two of the three CH tests in the treated and control groups. (or, if more than three experiments are performed, most of the experiments) at a given dose [see, e.g., Int. Arch. Allergy 38: 246-259 (1970)].

All of the compounds of Formula I listed in Table A below were effective at a dose of 50 mg / kg in two of three tests performed at a dose of 50 mg / kg unless otherwise indicated (see note following table). The minimum effective dose (i.e., the lowest effective dose at which a compound is still effective as defined above) is given in Table A for each compound. The number of the example for each compound illustrates the process or methods of preparation of the compound to which the example relates.

"The table

Example Name of compound Minimum effective dose (mg / kg) 36 2- (3,4-dichlorophenyl) -4-methyl- [l] - benzopyrano [4,3-c] pyrazol-3- (2H) -one 0.3 37 2- (4-fluorophenyl) -4-methyl- [l] benzenesulfonic benzopyrano [4,3-c] pyrazol-3 (2H) -one 1 38 2- (3-chlorophenyl) -4-methyl- [l) benzo pyrano [4,3-c] pyrazol-3 (2H) -one 3 39 2- (4-methoxyphenyl) -4-methyl [l] -be- benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 40 2- (4-chlorophenyl) -4-ethyl [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 41 ethyl-2- (4-chlorophenyl) -3-oxo-2,3- dihydro [l] benzopyrano [4,3-c] PIR azole-4-acetate 3 42 reference examples 4-Methyl-2-phenyl [1-benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 (a) 43/96 4-Methyl-2- (4-methyl-phenyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 10 44 2- (4-Bromo-phenyl) -4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 1 45 2- (3-Chloro-4-fluoro-phenyl) -4-methyl [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 0.3 46 2- (3-Chloro-4-methyl-phenyl) -4-methyl [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 3 47 4-Methyl-2- (4-trifluoromethyl-phenyl) [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 1 48 2- (4-chlorophenyl) -7-fluoro-4-methyl- [L] benzopyrano [4,3-c] pyrazole 3 (2H) -one 50 49 8-chloro-2- (4-chlorophenyl) -4-methyl- [L] benzopyrano [4,3-c] pyrazole 3 (2H) -one 50 50 2- (4-Chloro-phenyl) -4,8-dimethyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 51 2- (4-Chloro-phenyl) -9-methoxy-4-methyl- [1 H -benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 52 2- (4-chlorophenyl) -4,9-dimethyl- [L] benzopyrano [4,3-c] pyrazole 3 (2H) -one 50

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Example Name of compound Minimum effective dose (mg / kg) 53 ethyl [2- (4-fluorophenyl) -3-oxo-2,3- dihydro- [l] benzopyrano [4,3-c] PIR azole-4-acetate] 3 54 2- (4-chlorophenyl) -8-fluoro-4-methyl- [L] benzopyrano [4,3-c] pyrazole 3 (2H) -one 0.1 55 7-chloro-2- (4-chlorophenyl) -4-methyl- [L] benzopyrano [4,3-c] pyrazole 3 (2H) -one 50 56 2- (4-chlorophenyl) -8-hydroxy-4-me- methyl- [l] benzopyrano [4,3-c] pyrazole 3 (2H) -one 50 57 4-methyl-2- [4- (methylthio) phenyl) - [l] - benzopyrano [4,3-c] pyrazol-3 (2H) - you 3 58 2- (4-chlorophenyl) -9-ethoxy-4-methyl- [L] benzopyrano [4,3-c] pyrazole 3 (2H) -one 3 59 2- (4-Chloro-phenyl) -4-methyl-8-nitro [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 60 2- (4-Chloro-phenyl) -8-ethyl-4-methyl [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 61 6-Chloro-4-methyl-2-phenyl [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 62 2- (4-chloro-phenyl) -6-fluoro-4-methyl- [L] benzopyrano [4,3-c] pyrazole 3 (2H) -one 50 63 2- (4-Chloro-phenyl) -6,8-difluoro-4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 64 4-bromomethyl-2- (4-chloro-phenyl) - [l] - benzopyrano [4,3-c] pyrazol-3 (2H) - you 50 65 4-Chloromethyl-2- (4-chlorophenyl- [l] - benzopyrano [4,3-c] pyrazol-3 (3H) - you 3 66 2- (4-Chloro-phenyl) -6-methoxy-4-methyl [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 67 4-methyl-2- [4- (methylsulfinyl) -phenyl- phenyl] - [l] benzopyrano [4,3-c] PIR azole-3 (2H) -one 50 69 2- (4-chlorophenyl) -4- (methylthio me- methyl) - [l] benzopyrano [4,3-c] pyrazole 3 (2H) -one 3 74 [2- (4-chlorophenyl) -3-oxo-2,3-dihydroisoindol dihydro- [l] benzopyrano [4,3-c] pyrazole 4] acetamide 50 75 ethyl [2- (4-chlorophenyl) -α-methyl-3-oxo-2,3-dihydro- [1H-benzopyrano [4,3-c] pyrazole-4-acetate] 50 76 propyl [2- (4-chloro-phenyl) -3-oxo-2,3-dihydro- [1] benzopyrano [4,3c] pyrazole-4-acetate] 0.3

Example Name of compound Minimum effective dose (mg / kg) 77 isopropyl [2- (4-chlorophenyl) -3-oxo-2,3-dihydro [1] benzopyrano [4,3c] pyrazole acetate] 0.3 78 2- (4-kl6r-phenyl) -4-cyclopropyl [L] benzopyrano [4,3-c] pyrazole 3 (2H) -one 50 79 methyl [2- (4-chlorophenyl) -3-oxo-2,3- dihydro- [l] benzopyrano [4,3-c] PIR azole-4-acetate] 3 80 2- (4-chlorophenyl) -4- (ethylthio-methylthiazole) - [L] benzopyrano [4,3-c] pyrazole 3 (2H) -one 50 81 [2- (4-Chloro-phenyl) -4-methyl-3-oxo-2,3-dihydro- [1] benzopyrano [4,3c] pyrazol-9-yl] -acetate 50 82 [2- (4-chlorophenyl) -4-methyl-3-oxo- 2,3-dihydro- [l] benzopyrano [4,3- c] pyrazol-8-yl] acetate 50 (b) 83 2- (4-chlorophenyl) -4- (2-oxopropyl) - [L] -benzopyrano [4,3-c] pyrazole 3 (2H) -one 3 84 2- (4-chlorophenyl) -9-hydroxy-4-me- methyl- [l] benzopyrano [4,3-c] pyrazole 3 (2H) -one 3 85 2- [4-chloro-phenyl) -7-hydroxy-4-me- methyl- [l] benzopivano [4,3-c] pyrazole 3 (2H) -one 50 86 2- (4-chlorophenyl) -6-hydroxy-4-me- methyl- [l] benzopyrano [4,3-c] pyrazole 3 (2H) -one 50 87 2- (4-chlorophenyl (4-methylsulfonyl methyl) - [l] benzopyrano [4,3-c] PIR azole-3 (2H) -one 50 88 2- (4-Chloro-phenyl) -4- (methylsulfinylmethyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 89 [2- (4-Chloro-phenyl) -4-methyl-3-oxo-2,3-dihydro- [1] benzopyrano [4,3c] pyrazol-8-yl] -propionate 3 90 [2- (4-Chloro-phenyl) -4-methyl-3-oxo-2,3-dihydro- [l] benzopyrano [4,3c] pyrazol-8-yl] -butyrate 3 91 92 93 95 2- (4-chlorophenyl) -4-methyl [l] benzo- pyrano [4,3-c] pyrazol-3 (2H) -one 0.1 97 4-Methyl-2- [4- (trifluoromethyl) phenyl] -1,4-dihydro- [1 H -benzopyrano [4,3-c] pyrazol-3 (2H) -one 3 98 2- (3-Chloro-phenyl) -4-methyl-1,4-dihydro- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 3 99 2- (3,4-dichlorophenyl) -4-methyl-1,4- dihydro- [l] benzopyrano [4,3-c] PIR azole-3 (2H) -one 50

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Example Name of compound Minimum effective dose (mg / kg) 100 2- (4-chlorophenyl) -4-methyl-1,4- dihydro- [l] benzopyrano [4,3-c] PIR azole-3 (2H) -one 3 (C) 101 2- (4-fluorophenyl) -4-methyl-1,4- dihydro- [l] benzopyrano [4,3-c] PIR azole-3 (2H) -one 50 102 2- (4-chloro-phenyl) -3-oxo-2,3-dihydroisoindol dihydro- [l] benzopyrano [4,3-c] pyrazole 4-acetic acid 50 103 reference- example l- (4-chlorophenyl) -4- <l- [2- (4-chlorophenyl) -3-hydroxy-2,4-dihydro [l] benzopyrano [4,3-c] pyrazol-4-ylidene-methyl ] -e needleidene} -3- (2-hydroxyphenyl) -2-pyrazolidin-5-one 3 104 reference- example l- (3,4-dikl6r-phenyl) -4- (l- [2- (3,4-dichlorophenyl) -3-hydroxy-2,4-dihydro- [l] benzopyrano [4,3-c] pyrazol4 -ylidene methyl] ethyl idene) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one 50

Notes:

(a) effect in three of five tests at 50 mg / kg;

b) effect in one test at 50 mg / kg and in one test at 18 mg / kg;

(c) effect in one test at 50 mg / kg and effect in two tests at mg / kg.

The compounds of the present invention are effective in a variety of other in vivo assays that demonstrate their utility as immunomodulatory agents, particularly as immunosuppressive agents. The compounds were administered orally, parenterally or topically. We have found that certain compounds are effective in a test that determines their effect on humoral (body fluid related) immunity by altering the amount of anti-oxazolone antibody produced at the end of the oxazolone-induced skin hypersensitivity test (CH test) described above. and a Graft versus Hero test similar to that of Smith SR, Terminelli

C., Kipilman C. T and Smith Y. [J. Immunopharmacology 3 (2): 133-170 (1981)].

An embodiment of the process of the invention is illustrated by the following examples.

In the examples, the parts and percentages are by weight and the volume of the mixed solvent formulations. Compounds were characterized by elemental analysis and one or more spectroscopic techniques such as MMR, IR and mass spectroscopy.

Reference Example 1

To 74.9 g of (2-fluorophenyl) acetate is added portionwise 97.4 g of powdered aluminum chloride. The reaction mixture was slowly heated to 150 ° C and maintained at this temperature for 2 hours. The reaction mixture is then cooled to 40 ° C and the solid formed is added to 300 ml of ice water containing 5 ml of concentrated hydrochloric acid. The reaction mixture was steam distilled, the distillate cooled and extracted with ethyl acetate. The extract was dried and evaporated to give 3'-fluoro-2'-hydroxyacetophenone, m.p. 20 and 75-77'C.

Reference Example 2 A mixture of 5 g of 5'-fluoro-2'-hydroxyacetophenone and 130 ml of anhydrous toluene was stirred for 20 minutes.

A suspension of 6.17 g of sodium hydride (60% in a mineral oil suspension) in 130 ml of anhydrous toluene is added dropwise, and the mixture is refluxed under nitrogen. The mixture was refluxed for an additional 10 minutes while adding a solution of 15.7 ml of diethyl carbonate in 130 ml of anhydrous toluene over 25 minutes. The reaction mixture was stirred and refluxed for 4 hours. The reaction mixture was cooled and poured into ice-cooled 700 ml of 2M hydrochloric acid. The solid thus obtained is filtered off and dissolved in 325 ml of a 4M aqueous sodium hydroxide solution. The solution was washed with ether and acidified with 5M hydrochloric acid. The resulting solid product was filtered off, washed with water and dried to give 6-fluoro-4-hydroxycoumarin, m.p. 250-251 ° C.

3-6. PREPARATION

In a similar manner to that described in Example 2, compounds of formula IX are prepared from compounds of formula XII as shown in Table 1 below.

Table 1

Example (XII) Quantity of reagents Reflux Time (Hours) Compound IX has an op. ('C) Megjegyzé- sek r ₉ Rio (XII) (G) Sodium hydroxide added anhydride (G) Diethyl carbo sodium (G) Total toluene (ml) 3 3-F H 12.0 8.45 18.4 450 24 246-248 (1) (2) (3) 4 5-C ₂ H ₅ H 40.0 22.0 58.5 450 20 190-192 5 3-OCH ₃ H 14.3 7.77 20.3 450 24 244-246 (4) 6 3-F 5-F 14.0 7.32 19.5 480 . 4 236-240

Notes

1. Recrystallized from industrial methylated alcohol

2. A 50% dispersion of sodium hydride in mineral oil was used

3. The starting compound was prepared according to Example 1

4. recrystallized from propan-2-ol

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In each of the starting compounds of formula XII, R ₁₅ is -COCH ₃ , R ₉ and R _{10 are as} defined in Table 1.

3-6. The compounds of formula IX prepared according to Examples 1 to 8 are as follows:

Example 3 8-Fluoro-4-hydroxycoumarin

Example 4 6-Ethyl-4-hydroxycoumarin

Example 5 4-Hydroxy-8-methoxy-coumarin

Example 6 6,8-Difluoro-4-hydroxycoumarin.

Reference Example 7

(a) 34 g of 2-fluoro-6-methoxybenzonitrile are added in portions to a suspension of methyl magnesium iodide (6.5 g) and methyl iodide (38.4 g) in toluene (300 ml) under nitrogen, with stirring for 10-15 minutes. The reaction mixture was stirred and refluxed for 18 hours, then cooled to room temperature and 200 ml of 3M hydrochloric acid was added. This mixture was stirred and refluxed for 18 hours, cooled to room temperature and the organic layer separated. The aqueous phase was extracted with food and the combined ether and toluene extracts were washed with water, dried and evaporated to give 41.1 g of an oil. To a solution of 36 g of oil in 250 ml of dichloromethane was added 35.7 g of boron tribromide in 60 ml of dichloromethane over 25 minutes at -70 to -80 ° C. The reaction mixture was stirred at -80 ° C for 10 minutes and then allowed to warm to 0 ° C. Water (100 mL) was added and the temperature was kept below 10 ° C. The organic layer was separated, washed, dried and evaporated to give an oil which was distilled under reduced pressure. The product is 2'-fluoro-6'-hydroxyacetophenone boiling at 170-172 ° C / 0.27 mbar.

b) To a suspension of 17.1 g of sodium hydride (60% mineral oil dispersion) in 400 ml of anhydrous toluene is added 30 g of 2'-fluoro-6'-hydroxyacetophenone under stirring under nitrogen at reflux for 30 minutes. The reaction mixture was refluxed for a further 20 minutes while 50.8 g of diethyl carbonate was added dropwise over 10 minutes. The resulting mixture was heated to reflux for 20 hours with stirring. The reaction mixture was cooled to room temperature and water (150 mL) was added dropwise. The aqueous phase was separated, washed with ether and acidified with concentrated hydrochloric acid. The precipitate was filtered off, washed with water, dried and recrystallized from ethyl acetate to give 5-ethoxy-4-hydroxycoumarin, m.p. 110-111 ° C.

c) A mixture of 4.2 g of 5-ethoxy-4-hydroxycoumarin and 3.7 g of 4-chlorophenylhydrazine in 20 ml of xylene is heated at reflux for 6 hours while removing water from the reaction. The mixture was cooled to room temperature and the xylene removed under reduced pressure. The residue was taken up in 50 ml of methanol and 50 ml of concentrated hydrochloric acid

After refluxing for 2.5 hours, it was cooled to room temperature. The reaction mixture is then evaporated to dryness under reduced pressure and the residue is triturated with water. This gives a solid product which is dried, 1- (4-chlorophenyl) -3- (6-ethoxy-2-hydroxyphenyl) -2-pyrazolin-5-one.

Reference Example 8

a) A mixture of 17.2 g of 4-hydroxycoumarin and 18.8 g of 3,4-dichlorophenylhydrazine in 174 ml of anhydrous toluene

The mixture was heated at reflux for 4.25 hours while the water formed during the reaction was removed. The reaction mixture was allowed to cool and was allowed to stand at room temperature for 16 hours and then filtered. Thus, 1- (3,4-dichlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one and

A mixture of 4- [2- (3,4-dichlorophenyl) hydrazino] coumarin is obtained. The solid was heated with dichloromethane (about 500 mL), filtered hot and the liquid cooled to precipitate the solid product 1- (3,4-dichlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one. on, m.p. 196-200 'C.

9-32. PREPARATION

In a manner similar to that described in Example 8, compounds of formula IV are prepared by reacting compounds of formula VIII with compounds of formula IX as shown in Table 2. R ₇ and R _{8 in} Formula VIII and R ₉ and R _{10 in} Formula IX are shown in Table 2.

Table 2

Example (VIII) (Ix) Quantity of reagents Return time (hours) Compound (IV): m.p. Megjegyzé- sek R r ₈ r ₉ Rio (IX) (G) (VIII) (G) Toluene (Ml) 9 F H H H 15.0 11.7 153 4.2 170-173 10 H cl H H 5.03 4.86 50 2.0 146-148 (1) (2) 11 OCH ₃ H H H 23.1 21.7 500 2.0 133-135 (1) (2) 12 H H H H 5.62 4.12 50 2.0 119-121 (3) 13 ch ₃ H H H 13.4 11.1 100 2.0 180-182 (1) (2) 14 Br H H H 11.6 20.1 122 2.2 195-198 15 F cl H H 6.5 9.7 100 3.5 191-193 16 ch ₃ cl H H 2.0 2.7 10 4.0 157-159 (4) 17 cf ₃ H H H 1.97 3.0 ¹⁵ 4.0 174-177 (4)

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Example (VIII) (IX) Quantity of reagents Return time (hours) Compound (IV): m.p. Megjegyzé- sek r ₇ r ₈ r ₉ Rio (IX) (G) (VIII) (G) Toluene (Ml) 18 cl H H 7-F 1.0 1.18 15 4.0 172-174 (4) 19 cl H H 6-C1 1.96 2.14 15 4 217-221 20 Cl ..... H H 6-CH ₃ 17.6 21.4 150 4 232-234 21 cl H H 5-CH ₃ 5.0 6.07 55 3 183-185 (5) (6) 22 cl H H 6-F 6.0 7.83 60 2.5 180-183 (7) 23 cl H H 7-C1 2.10 2.25 35 3 198-199 (4) 24 cl H H 6-OCH ₃ 9.20 15.2 82 7.5 197-199 (8) 25 sch ₃ H H H 8.46 12.1 100 1 138-140 (9) 26 cl H H 7-OCH ₃ 10.0 11.0 140 5 189-190 (4) 27 cl H H 6-NO ₂ 7.3 10.5 100 8 220 (10) 28 cl H H 6-C ₂ H ₅ 5.5 4.9 120 4 192-194 (11) 29 H H H 8-C1 6.74 5.56 200 24 208-210 (12) 30 cl H H 8-F 4.5 5.35 100 24 219-221 (2) 31 cl H H 8-OCH ₃ 3.25 3.62 100 24 204-206 (12) 32 cl H 6-F 8-F 4.4 4.85 100 1 229-232 (4)

Notes

1. After refluxing, the solution was allowed to cool and the solvent was evaporated and the resulting solid was heated with dichloromethane.

2. recrystallization from acetonitrile

3. recrystallization from cyclohexane

4. Evaporate the dichloromethane extract to dryness

5. The starting material is a mixture of 5-methyl-4-hydroxycoumarin and 7-methyl-4-hydroxycoumarin

6. The desired compound (IV) is obtained by fractional crystallization of isomer mixtures from dichloromethane.

7. Allow the reaction mixture to cool and filter, then concentrate the filtrate until the product crystallizes.

8. The reaction mixture is filtered to give compound (IV)

9. The dichloromethane extracts were evaporated and the residue was triturated with ether.

10. The catalyst is p-toluenesulfonic acid

11. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was recrystallized from ethyl acetate.

12. The crude product is recrystallized from toluene instead of dichloromethane

9-32. Compounds of formula (IV) prepared according to Examples 1 to 4 are the following.

Example Compound 18 1- (4-Chloro-phenyl) -3- (4-fluoro-2-hydroxy-phenyl) - 2-pyrazolin-5-one 1- (4-chlorophenyl) -3- (5-chloro-2-hydroxyphenyl) -2- 9 l- (4-fluorophenyl) -3- (2-hydroxyphenyl) -2-PIR 19 10 quinazolin-5-one l- (3-chlorophenyl) -3- (2-hydroxyphenyl) -2-PIR 45 20 pyrazolin-5-one l- (4-chlorophenyl) -3- (2-hydroxy-5-methylphenyl) - 11 quinazolin-5-one 3- (2-hydroxy-phenyl) -l- (4-methoxyphenyl) -2-PIR 21 2-pyrazolin-5-one l- (4-chlorophenyl) -3- (2-hydroxy-6-methylphenyl) - 12 quinazolin-5-one 3- (2-hydroxyphenyl) -l-phenyl-2-pyrazolin-5-one 50 22 2-pyrazolin-5-one 1- (4-chlorophenyl) -3- (5-fluoro-2-hydroxyphenyl) - 13 14 15 3- (2-hydroxy-phenyl) -l- (4-methylphenyl) -2-PIR quinazolin-5-one l- (4-bromophenyl) -3- (2-hydroxyphenyl) -2-PIR quinazolin-5-one l- (3-chloro-4-fluorophenyl) -3- (2-hydroxyphenyl) - 55 23 24 2-pyrazolin-5-one 3- (4-Chloro-2-hydroxy-phenyl) -1- (4-chloro-phenyl) -2-pyrazolin-5-one l- (4-chlorophenyl) -3- (2-hydroxy-5-methoxyphenyl) -2-pyrazolin-5-one 16 17 2-pyrazolin-5-one 1- (3-Chloro-4-methyl-phenyl) -3- (2-hydroxy-phenyl) - 2-pyrazolin-5-one 3- (2-Hydroxy-phenyl) -1- [4- (trifluoromethyl) -phenyl] -2-pyrazolin-5-one 60 25 26 3- (2-hydroxy-phenyl) -l- [4- (methylthio) phenyl] - 2- pyrazolin-5-one 1- (4-Chloro-phenyl) -3- (2-hydroxy-4-methoxyphenyl) -2-pyrazolin-5-one

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Example Compound 27 1- (4-chlorophenyl) -3- (2-hydroxy-5-nitrophenyl) - 2-pyrazolin-5-one 28 l- (4-chlorophenyl) -3- (5-ethyl-2-hydroxyphenyl) -2- pyrazolin-5-one 29 3- (3-chloro-2-hydroxyphenyl) -l-phenyl-2-pyrazoline 5-one 30 1- (4-chlorophenyl) -3- (3-fluoro-2-hydroxyphenyl) - 2-pyrazolin-5-one 31 l- (4-chlorophenyl) -3- (2-hydroxy-3-methoxy-Fe phenyl) -2-pyrazolin-5-one 32 l- (4-chlorophenyl) -3- (3,5-difluoro-2-hydroxy-Fe phenyl) -2-pyrazolin-5-one.

Reference Example 33

a) A mixture of 10.8 g of 4-hydroxycoumarin and 9.5 g of 4-chlorophenylhydrazine in 110 ml of anhydrous toluene is heated at reflux for 1.5 hours while removing water from the reaction. The mixture was allowed to stand overnight at room temperature and the resulting solid was filtered off. This product is boiled in about 200 mL of dichloromethane, filtered hot and recrystallized from industrial methylated alcohol to give 4- [2- (4-chlorophenyl) hydrazino] coumarin, m.p. 226-229 ° C.

b) A mixture of 2.86 g of 4- [2- (4-chlorophenyl) hydrazino] coumarin, 250 ml of ethanol and 2 ml of 5 M hydrochloric acid

Reflux with stirring for 21.5 hours. The reaction mixture is then cooled and filtered. The filtrate was evaporated and the residue partitioned between dichloromethane and water. The dichloromethane extracts were combined, dried and concentrated to give 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one, mp 182-187 ° C.

Reference Example 34

a) A mixture of 6.5 g of 4-hydroxy-5-methoxycoumarin, 7.3 g of 4-chlorophenylhydrazine and 66 ml of anhydrous toluene is heated to reflux with stirring while removing water from the reaction. The reaction mixture was cooled and the resulting solid was filtered off, 4- [2- (4-chlorophenyl) hydrazino] -5-methoxycoumarin, m.p. 206-209 ° C.

b) A mixture of 1.58 g of 4- [2- (4-chlorophenyl) hydrazino] -5-methoxycoumarin, 1 ml of a 5 M aqueous sodium hydroxide solution and 100 ml of industrial methylated alcohol is refluxed for 4 hours. The reaction mixture was cooled and filtered, the filtrate was evaporated to dryness and the residue partitioned between dichloromethane and water. The dichloromethane layer was separated, dried and concentrated and then filtered to give 1- (4-chlorophenyl) -3- (2-hydroxy-6-methoxyphenyl) -2-pyrazolin-5-one, m.p. 185-188'C.

Reference Example 35

2.3 g of 3- (2-hydroxyphenyl) -1- (4-methylthiophenyl) -2-pyrazolin-5-one (Example 25), 1.7 g of 80% 3-chloroperoxybenzoic acid and 172 ml of dichloromethane were stirred at room temperature for 66 hours. The reaction mixture was washed with saturated sodium bicarbonate solution, then water, dried and evaporated. The residue is recrystallized from toluene / petroleum ether (b.p. 62-68 'C) to give 3- (2-hydroxyphenyl) -1- (4-methylsulfinylphenyl) -2-pyrazolin-5-one, m.p.

Example 36

A mixture of 2.0 g of 1- (3,4-dichlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one (Example 8) and 3.41 ml of triethyl orthoacetate Heat at -10 ° C for 10 minutes with stirring. The mixture was then allowed to cool to room temperature and maintained at this temperature for 16 hours. Triturate with ether, filter the solid, and dry to give 2- (3,4-dichlorophenyl) -4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one. mp 207-211 ° C.

37-68. example

Compounds (II) were prepared in a manner similar to that described in Example 36 by reacting (IV) with (Va). The results are shown in Table 3. The substituents R ₇ , R ₈ , R ₉ and R _{10 of} the compound (IV) are shown in Table 3. In Table 3, unless otherwise noted, R _1g is R ₅ R ₆ CH- and YC ₂ H ₅ -. The number in the brackets in the number of examples refers to the example in which Compound (IV) was prepared. Unless otherwise indicated, the amount of compound (Va) is expressed in milliliters.

Table 3

Example (ARC) (Va) reagents The amount warming time (minute) Melting point (11) (° C) remarks ing r ₇ ^R 8 r ₉ Rio ^R 18 ARC (G) Va (Ml) 37 (9) F H H H ch ₃ 3.0 6.0 10 183-187 38 (10) H cl H H ch ₃ 3.52 6.75 60 171-173 (1) 39 (11) and ₃ H H H ch ₃ 6.0 11.7 60 177-179 (2) 40 (9am) cl H H H c ₂ h ₅ 4.29 9.0 10 167-171 41 (9am) cl H H H ch ₂ cooc ₂ h ₅ 2.87 7.02 10 159-161

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Example (ARC) (Va) reagents The amount warming time (minute) Melting point ('C) of (II) remarks ing r ₇ Rs Rs Rio ^R 18 ARC (G) Va (Ml) 42 reference examples (12) H H H H ch ₃ 2.52 5.49 60 163-165 (1) 43 (13) ch ₃ H H H ch ₃ 6.76 14.0 60 162-164 (3) 44 (14) Br H H H ch ₃ 4.0 6.6 20 196-199 45 (15) F cl H H ch ₃ 3.1 11.2 20 204-207 46 (16) ch ₃ cl H H ch ₃ 1.0 1.79 15 188-190 (5) 47 (17) cf ₃ H H H ch ₃ 0.5 0.86 15 199-200 (5) 48 (18) cl H H 4-F ch ₃ 0.5 0.91 15 194-198 (5) 49 (19) cl H H 5-C1 ch ₃ 0.65 1.1 10 190-192 50 (20) cl H H 5-CH ₃ ch ₃ 3.00 8.2 10 195-197 51 (34) cl H H 6-OCH ₃ ch ₃ 1.10 1.9 25 226-230 52 (21) cl H H 6-CH ₃ ch ₃ 0.50 0.9 15 208-210 53 (9) F H H H ch ₂ cooc ₂ h ₅ 1.20 3, Ig 15 152-154 54 (22) cl H H 5-F ch ₃ 1.52 2.75 10 187-189 55 (23) cl H H 4-C1 ch ₃ 1.00 1.7 15 230-231 56 (82a) cl H H 5-OH ch ₃ 1.40 5.6 10 315-319 57 (25) sch ₃ H H H ch ₃ 3.00 5.5 10 174-176 58 (7c) cl H H 6-OC ₂ H ₅ ch ₃ 2.8 4,9g 35 216-218 59 (27) cl H H 5-NO ₂ ch ₃ 7.0 15.0 90 257-258 (6) 60 (28) cl H H 5-C ₂ H ₅ ch ₃ 3.7 5,8g 30 193-194 61 (29) H H H 3-C1 ch ₃ 3.0 10.0 30 209-211 (4) (7) 62 (30) cl H H 3-F ch ₃ 2.0 8.0 30 232-234 (4) (7) 63 (32) cl H 3-F 5-F ch ₃ 1.05 1.8 10 214-216 ,, 64 (9am) cl H H H CH ₂ Br 8.0 20.0 g 50 207-208 (8) 65 (9am) cl H H H CH ₂ Cl 1.43 2,31g 10 237-240 (9) 66 (31) cl H H 3-OCH ₃ ch ₃ 3.0 5.2 30 243-245 (4) 67 (35) soch ₃ ch ₃ H H H 0.7 1.2 20 228-230 68 (26) cl H H 4-OCH ₃ ch ₃ 2.30 3.91 15 201-204

Notes

1. recrystallization from isopropanol

2. recrystallization from acetonitrile

3. recrystallization from propanol

4. The reagents were heated to 135-145 ° C

5. The reagents were heated to 125 ° C

6. The product is purified by dissolving in dichloromethane, diluting with industrial methylated alcohol, filtering and evaporating the filtrate.

7. Recrystallize from ethyl acetate

8. Toluene is added to the reagents and the mixture is refluxed

9. In formula (Va), Y is methyl

Example 69 a) "The operation

A solution of 100 g of methylthioacetonitrile and 47 ml of methanol in 644 ml of anhydrous food is saturated with hydrochloric acid at 0-5 ° C. The mixture was allowed to warm to room temperature over 16 hours. The solid product thus obtained is filtered off, washed and dried to give methyl methylthioacetimidate hydrochloride as a sticky solid.

(b) 'Operation B')

A mixture of methyl methylthioacetimidate hydrochloride 69a (69a) and methanol (551 ml) was heated at 35-45 ° C for 3 hours.

After stirring at room temperature, allow to stand at room temperature for 72 hours. The reaction mixture was filtered and the filtrate was evaporated to give an oil which was low in solids and removed by filtration on a cotton pad to give trimethyl ortho-methylthioacetate as an oil, b.p. 96-104 ° C. , 6 mbar).

(c) operation 'C'

To 2.87 g of 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one (Example 91a) is added 5 ml of trimethyl ortho (methylthio) acetate and the mixture is added to the mixture. 10 minutes 135—

After heating at 145 ° C, it is triturated with 10 ml of ether and filtered. The residue was washed with excess water and then with excess ether to give 2- (4-chlorophenyl) -4- (methylthiomethyl) - [l] benzopyrano [4.35 c] pyrazole-3 (2H) -. m.p. 215-217 ° C.

70-73. PREPARATION

Similarly as described in Example 69, steps A and B, the compounds of formula Va were prepared as shown in Table 4.

Table 4 Step A - Preparation of Imidate Hydrochlorides

Example nitrile Quantity (G) Alcohol Quantity Amount of ether (ml) 70 NCCH ₂ CONH ₂ 79.8 C ₂ H ₅ OH 110 ml 536 (2) 71 NCCH (CH ₃ ) CO ₂ C ₂ H ₅ 30.5 c ₂ h ₅ oh 14 ml 134 (3) (4) 72 NCCH ₂ CO ₂ C ₃ H ₇ (n) 30.5 (n) C ₃ H ₇ OH 18.5 ml 134 (3) 73 NCCH ₂ CO ₂ C ₃ H ₇ (i) 15.0 CH ₃ OH 4.2 g 70 (1)

Step B - Production of Orthoesters

Example Alcohol The amount of alcohol Temperature ° C Heating time (hours) The boiling point of (Va) 70 C ₂ H ₅ OH 750 ml (l) 40-45 22 decomposes on heating 71 c ₂ h ₅ oh 180 ml (1) 45-50 24 130-142 ° C (30 mm Hg) 72 (n) C ₃ H ₇ OH 180 ml (1) 45-50 24 165-175 ° C (5mmHg) 73 CH ₃ 0H 53 ml (5) 30-40 16 180-190 ° C (10mmHg)

Notes

1. At the end of the reaction, ether is added to the mixture

2. To increase the solubility, add 110 ml of anhydrous dioxane and 250 ml of ether at the end of the reaction.

3. The reaction mixture is evaporated to give the imidate

4. Crystallized from ether

5. At the start of the reaction, ether (290 ml) was added to the starting material

The compounds prepared according to Table 4, Procedure B are as follows:

Example 70 Triethyl ortho (carbamoyl) acetate

Example 71 Triethyl ortho (2-ethoxycarbonyl) propionate

Example 72 Tripropyl ortho (propoxycarbonyl) acetate

Example 73 Trimethyl ortho (isopropoxycarbonyl) acetate.

74-77. example

In a similar manner to that described in Example 69, Step C, compounds of formula II were prepared from compounds Va and IV. The results are shown in Table 5. In Table 5, R ₁₈ is R ₁₃ -CH and in compounds (IV) R ₇ , R ₈ , R ₉ and

Rio has the meaning given in Table 5.

Table 5

Example (ARC) (Va) (ARC) How much- of (G) (Va) How much- of (G) Heating time (minutes) Melting point ('C) of (II) remarks acquisitions r ₇ Rs r ₉ Rio ^R 1S 74 cl H H H CH ₂ CONH ₂ 2.87 6.15 10 253-256 (1) (4) 75 cl H H H CH (CH ₃ ) COOC ₂ H ₅ 2.87 7.44 30 130-134 (2) (4) 76 cl H H H CH ₂ COOC ₃ H ₇ (n) 2.87 8.7 40 138-140 (2) (3) 77 cl H H H CH ₂ COOC ₃ H ₇ (i) 0.46 2.0 15 124-126 (1)

Notes

1. Reagents are heated to 125-135 ° C

2. The reaction mixture is cooled and triturated with industrial methylated alcohol and the product is filtered off

3. Y - nC ₃ H ₇ in formula (Va)

4. Y = C ₂ H ₅ in formula (Va)

HU 208 977 Β

Example 78

a) A mixture of 1.43 g of 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one (Example 91a) and 7.5 ml of acetic anhydride in 0.41 g of anhydrous sodium acetate, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into a 9: 1 mixture of water and petroleum ether boiling at 62-68 ° C. The solid product is filtered off, washed with water and petroleum ether (b.p. 62-68 ° C) and dried to give

1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -5-pyrazolyl acetate, m.p. 108-110 ° C.

b) A solution of 3.29 g of 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -5-pyrazolyl acetate in 50 ml of anhydrous tetrahydrofuran and 3 ml of triethylamine is stirred at 0-5 ° C. 2 ml of cyclopropanecarbonyl chloride were added dropwise and the reaction mixture was allowed to warm to room temperature with stirring for 16 hours. The mixture was then poured into water (10 volumes) and extracted with ethyl acetate. The extracts were washed with water, dried and evaporated to give 2- [5-acetoxy-1- (4-chlorophenyl) 3-pyrazolyl] phenylcyclopropanecarboxylate as an oily product.

c) A mixture of {2- [5-acetoxy-1- (4-chlorophenyl) -3-pyrazolyl] phenyl} cyclopropanecarboxylate of Example 78b, 1 ml of piperidine and 30 ml of anhydrous ethanol was heated at reflux for 2 hours. . The precipitated solid was filtered off, washed with ethanol and dried. so we get a

2- (4-chlorophenyl) -4-cyclopropyl- [1] benzopyrano [4,3-c] pyrazol- (2H) -one, m.p. 240-243 ° C.

Example 79

a) In a manner similar to Example 78a, 1.9 g of 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one (Example 91a), 10 ml of butyric anhydride and 0. A mixture of 73 g of sodium butyrate gives 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) 5-pyrazolyl butyrate, m.p. 119-122 ° C.

b) For a mixture of 3.57 g of 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -5-pyrazolyl butyrate in 50 ml of tetrahydrofuran and 1.5 ml of triethylamine, 1.2 ml of methyl malonyl chloride was added dropwise with stirring. The reaction mixture was stirred for 24 hours at room temperature, and then 0.6 ml of methyl malonyl chloride and 0.75 ml of triethylamine were added. The reaction mixture was stirred for 24 hours at room temperature and then treated as described in Example 78b. This gives an oil from which the unreacted starting material is triturated with ether.

c) The above product is heated to reflux in a mixture of 25 ml of anhydrous toluene and 1 ml of piperidine. The reaction mixture was cooled and the product filtered off. There was thus obtained methyl [2- (4-chlorophenyl) -3-oxo-2,3-dihydro [l] benzopyrano [4,3-c] pyrazole-4-acetate), m.p. 170-172 ° C. .

Example 80

To a mixture of 3.57 g of 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -5-pyrazolyl butyrate (Example 79a) in 50 ml of anhydrous tetrahydrofuran and 1.5 ml of triethylamine Ethyl thioacetyl chloride (1 ml) was added dropwise with stirring at 1 ° C. After stirring at room temperature for 2 days, the reaction mixture was cooled to 0-5 ° C and additional 0.75 mL of triethylamine and 0.5 mL of ethyl thioacetyl chloride were added. The mixture was stirred for 16 hours at room temperature and treated in the same manner as in Example 78b. This gives a gummy material which is refluxed in 20 ml of anhydrous ethanol containing 1 ml of piperidine for 35 minutes. The reaction mixture was cooled and filtered to give 2- (4-chlorophenyl) -4- (ethylthiomethyl) [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. 167'C.

Example 81

a) 1.52 g of 1- (4-chlorophenyl) -3- (2-hydroxy-6-methoxyphenyl) -2-pyrazolin-5-one (Example 34), 2.54 g of aluminum chloride and of anhydrous xylene (100 mL) was stirred for 35 minutes. The reaction mixture was cooled, the xylene decanted, and 32.6 ml of 2M hydrochloric acid and ice were added to the resulting brown gum. The resulting solid product is filtered off, washed, dried and recrystallized from aqueous industrial methylated alcohol. There was thus obtained 1- (4-chlorophenyl) -3- (2,6-dihydroxyphenyl) -2-pyrazolin-5-one, m.p. 290293C.

b) A mixture of 1.36 g of 1- (4-chlorophenyl) -3- (2,6-dihydroxyphenyl) -2-pyrazolin-5-one, 6.75 ml of acetic anhydride and 0.37 g of sodium acetate at room temperature. stir for 1 hour. Then 0.74 g of sodium acetate was added and the mixture was stirred for an additional 16 hours. The reaction mixture was added to a 9: 1 mixture of water and petroleum ether boiling at 60-80 ° C. The precipitate was filtered off, dried and stirred in an ice-water bath in a mixture of 26 ml of anhydrous tetrahydrofuran and 1.42 ml of triethylamine, while 0.74 ml of acetyl chloride was added dropwise. The reaction mixture was stirred for 3.3 hours and then added to 10 volumes of water. The solid was filtered off and dried to give 1- (4-chlorophenyl) -3- (2,6-diacetoxyphenyl) -5-pyrazolyl acetate, m.p.

c) A mixture of [1- (4-chlorophenyl) -3- (2,6-diacetoxyphenyl) -5-pyrazolyl] acetate (1.2 g), piperidine (0.28 ml) and ethanol (5.5 ml) was refluxed for 30 minutes. The reaction mixture was cooled to give a solid which was filtered to give [2- (4-chlorophenyl) -4-methyl-3-oxo-2,3-dihydro [1] benzopyrano [4,3-c] pyrazole. 9-yl] acetate, m.p. 233-236 ° C.

Example 82

a) 5.5 g of 1- (4-chlorophenyl) -3- (2-hydroxy-5-methoxyphenyl) -2-pyrazolin-5-one (Example 24), 9.35 g of aluminum chloride and Anhydrous xylene (100 ml) was heated at 100 ° C for 1 hour with stirring and then treated in the same manner as in Example 8la. The product was crystallized from methanol to give 1- (4-chlorophenyl) 3- (2,5-dihydroxyphenyl) -2-pyrazolin-5-one, m.p. 220-225 ° C.

b) a mixture of 0.6 g of 1- (4-chlorophenyl) -3- (2,5-dihydroxyphenyl) -2-pyrazolin-5-one, 3 ml of acetic anhydride and 0.5 g of anhydrous sodium acetate reflux for one hour with stirring. The reaction mixture was poured into water and the product was extracted with ethyl acetate. Ethyl15

Evaporation of the acetate gave an oil which was refluxed in a mixture of 4 ml of anhydrous ethanol and 0.2 ml of piperidine for 3 hours. Upon cooling, the solid precipitates and is filtered to give [2- (4-chlorophenyl) -4-methyl-3-oxo-2,3-dihydro- [l] benzopyrano [4,3-c] pyrazole. 8l] -acetate, m.p. 192-194 ° C.

Example 83

To a mixture of 3.8 g of 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one (Example 91b) and 20 ml of xylene at 130-135 ° C over 15 minutes with stirring 2.85 g

A mixture of 2,2,6-trimethyl-4H-1,3-diox-5-en-4-one and 15 ml of xylene is added dropwise while the low-boiling material is distilled off. The reaction mixture was heated for 30 minutes with stirring and then 1.4 g of 2,2,6-trimethyl4H-1,3-diox-5-en-4-one in 7.5 ml xylene were added over 10 minutes. The reaction mixture was heated for 1 hour with stirring and then the xylene was removed under reduced pressure. The resulting solid residue was recrystallized from propan-2-ol to give 2- (4-chlorophenyl) -4- (2-oxopropyl) - [1] benzopyrano [4,3-c] pyrazole-3 (2H) -. ont., m.p. 167-168 ° C.

Example 84

0.50 g of 2- (4-chlorophenyl) -9-methoxy-4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 51) and 0.78 g. A mixture of aluminum chloride (g) in anhydrous xylene (4.8 ml) was placed in an oil bath preheated to 100-110 ° C for 35 minutes. The reaction mixture was cooled, 10 ml of 2M hydrochloric acid and ice were added, and the yellow solid was filtered to give 2- (4-chlorophenyl) -9-hydroxy-4-methyl- [1] benzopyrano [4,3-c]. ] -pyrazol-3 (2H) ont., m.p. 213-215 ° C.

Example 85

Similarly to Example 84, 1.0 g of 2- (4-chlorophenyl) -7-methoxy-4-methyl- [1] benzopyrano [4,3-c] pyrazol-3- (2H) -one (Example 1), 12 ml of anhydrous xylene and

A mixture of 1.7 g of aluminum chloride was heated at 100 ° C for 2 hours to give 2- (4-chlorophenyl) -7-hydroxy-4-methyl [1] benzopyrano [4,3-c] pyrazole-3 (2H) -one, m.p.> 300 ° C.

Example 86

Similarly to Example 84, 1.0 g of 2- (4-chlorophenyl) -6-methoxy-4-methyl- [1] benzopyrano [4,3c] pyrazol-3 (2H) -one (Example 66). ), A mixture of 1.7 g of aluminum chloride and 12 ml of anhydrous xylene was heated at 100 ° C for 3 hours and then recrystallized from N, N-dimethylformamide to give 2- (4-chlorophenyl) -. 6-hydroxy-4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p.> 300 ° C.

Example 87

1.5 g of 2- (4-chlorophenyl) -4- (methylthiomethyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 69c); A mixture of 8 g of 80% 3-chloroperoxybenzoic acid in 265 ml of dichloromethane was stirred at room temperature for 48 hours. Then, 0.2 g of 80% 3-chloroperoxybenzoic acid in 25 ml of dichloromethane was added to the reaction mixture and stirred for 48 hours. The reaction mixture was washed with saturated sodium bicarbonate solution, then water, dried and concentrated. The solid product was filtered off to give 2- (4-chlorophenyl) -4- (methylsulfonylmethyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. 240-243 '. C.

Example 88

1.5 g of 2- (4-chlorophenyl) -4- (methylthiomethyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 69c) and 0.9 g 80%

The mixture of 3-chloroperoxybenzoic acid was stirred in 172 ml of dichloromethane at room temperature for 60 hours. The product was filtered off to give 2- (4-chlorophenyl) -4- (methylsulfonylmethyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. 193-194. 'C.

Example 89

1.5 g of 2- (4-chlorophenyl) -8-hydroxy-4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 56), 45 ml A mixture of anhydrous pyridine and 0.9 ml of propionyl chloride was stirred in an ice bath and allowed to warm to room temperature over 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed several times with water, dried and evaporated to give a solid which was triturated with ether and crystallized from industrial methylated alcohol. [2- (4-Chloro-phenyl) -4-methyl-3-oxo-2,3-dihydro- [l] benzopyrano [4,3-c] pyrazol-8-yl] -propionate is obtained, m.p. 191-193 '. C.

Example 90

2.0 g of 2- (4-chlorophenyl) -8-hydroxy-4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 56), 50 ml To a mixture of dichloromethane and 2.2 ml of triethylamine, 1.64 ml of butyryl chloride is added dropwise with stirring at 0-5 ° C. After stirring for 20 hours at room temperature, the reaction mixture was washed with water, dried and concentrated under reduced pressure. The residue was triturated with ether and filtered to give [2- (4-chlorophenyl) methyl-3-oxo-2,3-dihydro- [1] benzopyrano [4,3-c] pyrazol-8-yl] butyrate. having a melting point of 170-173 ° C.

Example 91

a) A mixture of 14.3 g of 4-hydroxycoumarin and 18.9 g of 4-chlorophenylhydrazine in 150 ml of anhydrous toluene was refluxed for 2.5 hours while the water formed during the reaction was removed. The reaction mixture was allowed to cool to room temperature and filtered to give a solid, m.p. 183-185 DEG C., 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) 2-pyrazolin-5-one.

b) A mixture of 1.43 g of 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one and 2.74 ml of triethyl orthoacetate for 10 minutes at 130-135 ° C. while stirring. The reaction mixture was allowed to cool to room temperature, triturated with ether (10 mL), filtered and dried. There was thus obtained 2- (4-chlorophenyl) -4-methyl- [1] benzopyran. no [4,3-c] pyrazol-3 (2H) -one, m.p. 204-206 ° C.

Example 92

0.29 g of 1- (4-chlorophenyl) -3- (2-hydroxyphenyl) -2-pyrazolin-5-one (Example 91a), 0.25 g of sodium acetate and 1.5 ml of

The mixture of acetic anhydride was heated to reflux for 0.5 hours with stirring. The reaction mixture was then cooled to room temperature, diluted with water and extracted with ether. The extracts were washed with water, dried and evaporated to give a semi-crystalline gum. A mixture of this material and 0.08 ml of piperidine was refluxed in 2 ml of ethanol for 1.5 hours, then diluted with water and acidified with concentrated hydrochloric acid. The solid product is filtered off, m.p. 202-205 DEG C., 2- (4-chlorophenyl) -4-methyl- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one.

Example 93

0.8 g of 2- (4-chlorophenyl) -3-oxo-2,3-dihydro- [l] benzopyrano [4,3-c] pyrazole-4-acetamide (Example 74) and 25 ml of 75% sulfuric acid was heated at 100-120 ° C for 9 hours with stirring. The reaction mixture was poured onto 10 volumes of ice and the resulting solid was filtered off. 2- (4-chlorophenyl) -4-methyl- [1] benzopyrano [4,3c] pyrazol-3 (2H) -one, m.p. 204-206 ° C.

Reference Example 94

(a) Metal salt (2.24 g) is dissolved in methanol (24 ml), and ethyl formate (8.1 ml), dissolved in methanol (52 ml), is added. The reaction mixture was stirred at 0-5 ° C while 8.78 g of 6-fluoro-2-methyl-4-chromanone was added portionwise over 5 minutes. This mixture was stirred for 1 hour and allowed to stand at room temperature overnight. The solvent was evaporated and to the residue was added 5M sodium hydroxide solution to pH> 10 and partitioned between toluene and water. The separated aqueous phase was acidified with 2M hydrochloric acid to give a

6-fluoro-3-hydroxymethylene-2-methyl-4-chromanone, m.p. 68-73 ° C.

b) A mixture of 1.8 g of 6-fluoro-3-hydroxymethylene-2-methyl-4-chromanone, 0.49 g of hydroxylamine hydrochloride and 41 ml of glacial acetic acid is refluxed for 10 minutes. Water (40 mL) was added and the product filtered to give 8-fluoro-4-methyl-4H [1] benzopyrano [3,4-d] isoxazole, m.p. 84-87 ° C.

c) To a suspension of 0.125 g of 8-fluoro-4-methyl-4H- [1] benzopyrano [3,4-d] isoxazole in 2 ml of anhydrous ethanol is added 0.017 g of metal sodium in 0.4 ml of ethanol with stirring. The resulting solution was stirred for 3 hours, then acidified with 5M hydrochloric acid and diluted with water. On cooling, a solid precipitates, is filtered off and dried to give 6-fluoro-2-methyl-4-oxo-3-chromanecarbonitrile, m.p. 125-128 ° C.

d) A mixture of 1.1 g of 6-fluoro-2-methyl-4-oxo-3-chromanecarbonitrile and 50 ml of methanol of analytical purity was saturated with hydrochloric acid at 0-5 ° C and allowed to stand for 66 hours. The mixture was evaporated and the residue partitioned between water and ethyl acetate. The combined ethyl acetate extracts were dried and concentrated to give a solid which was filtered off. The product is 6-fluoro-2-methyl-4-oxo-3-chromanecarboxamide, m.p. 161-165 ° C.

(e) A mixture of 6-fluoro-2-methyl-4-oxo-3-chromanecarboxamide (0.467 g) and 4-chlorophenylhydrazine (0.298 g) in glacial acetic acid (1 ml) was heated at 110-115 ° C for 1 hour with stirring. After 45 minutes, additional 4-chlorophenylhydrazine (0.075 g) was added. The reaction mixture was cooled, diluted with ether, washed with water, dried and evaporated. The residue was purified by preparative thin layer chromatography on silica gel using toluene / glacial acetic acid (9: 1) as mobile phase. There was thus obtained 1- (4-chlorophenyl) -3- (5-fluoro-2-hydroxyphenyl) -2-pyrazolin-5-one, m.p. 178-182 ° C.

Example 95

To a suspension of 21.1 g of dimethylsulfide copper (I) bromide complex in 800 ml of anhydrous ethers in a nitrogen atmosphere at -10 - (- 15) ° C with stirring, 74 ml of a 1.4 molar solution of methyl lithium in ether are added. We are added. The resulting mixture was cooled to -40 'C, methyl 4-oxo-4H-chromene-3-carboxylate (7.0 g) in anhydrous ether (100 ml) was added dropwise and the reaction mixture was stirred at -40 ° C for 30 minutes. Saturated aqueous ammonium chloride solution (100 mL) was then added dropwise to the reaction mixture while maintaining the temperature at -40 - (- 20) C, allowing the mixture to warm to room temperature and extracting with ethyl acetate. The combined extracts were washed, dried and evaporated to give 8.6 g of a yellow oil. This oil

Dissolve 4.3 g of 4-chlorophenylhydrazine in 250 ml of toluene and reflux for 3 hours under nirogen while removing any water formed. The reaction mixture was cooled to room temperature and p-chloroanil (8.3 g) was added. The reaction mixture was refluxed under nitrogen for 2 hours with stirring, then cooled to room temperature and allowed to stand for 16 hours. The precipitated solid product was filtered off, washed with water and then with methylated industrial alcohol and ether to give 2- (4-chlorophenyl) 4-methyl-1,4-dihydro- [l] benzopyrano [4,3-c] pyrazole. -3- (2H) -one, m.p. 203-206 ° C.

Example 96

200 mg of 4-methyl-2- (4-methylphenyl) -1,4-dihydro [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 105), 0.15 g A mixture of p-chloroanil and 2 ml of dimethylsulfoxide was stirred at room temperature for 3 hours and then filtered. The filtered product was suspended in dimethyl sulfoxide, cooled and filtered to give 4-methyl-2- (4-methylphenyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. -160'C.

Example 97

1.10 g of 4-methyl-2- [4- (trifluoromethyl) phenyl] - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 47) with 22 ml of ethanol The slurry was stirred at 0-5 ° C with 0.24 g of sodium borohydride. The reaction mixture was stirred for 20 minutes while being allowed to warm to room temperature. The ethanol is decanted and added to a mixture of 180 ml of water and 20 ml of petroleum ether boiling at 60-80 ° C. The pH is adjusted to 4-5 with glacial acetic acid and the solid is filtered off. The solid was flash chromatographed17

Purify on silica gel (to remove starting material) using ethyl acetate / glacial acetic acid (9: 1) to elute the column. There is thus obtained 4-methyl-2- [4- (trifluoromethyl) phenyl] -1,4-dihydro [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. 145 'C.

Example 98

A suspension of 1.3 g of 2- (3-chlorophenyl) -4-methyl- [l] benzopyrano [4,3c] pyrazol-3- (2H) -one (Example 38) in 31 ml of ethanol was dissolved in 0-5 '. C is treated with 0.33 g of sodium borohydride with stirring. The reaction mixture was stirred at the above temperature for 22 minutes and then poured into a mixture of 9 volumes of water and 1 volume of petroleum ether boiling at 60-80 ° C with stirring. The insoluble starting material was removed by decantation, the pH was adjusted to 4-5 with glacial acetic acid, and the mixture was filtered. There was thus obtained 2- (3-chlorophenyl) -4-methyl-1,4-dihydro- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. 140-141 ° C.

Example 99

1.31 g of 2- (3,4-dichlorophenyl) -4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 36) and 28.5 ml The ethanol mixture was treated with 0.29 g of sodium borohydride in portions with stirring at 0-5 ° C, and the resulting mixture was stirred at the above temperature for 22 minutes. The solution was decanted from a small amount of solids and added to a 9: 1 mixture of water and petroleum ether boiling at 60-80 ° C under cooling and stirring. After filtration, the pH of the mixture was adjusted to 4-5 with glacial acetic acid. The filtered solid was washed, dried and recrystallized from industrial methylated alcohol to give 2- (3,4-dichlorophenyl) -4-methyl-1,4-dihydro- [1] benzopyrano [4,3 c] pyrazole-3 2H) -one, m.p. 147-150 ° C.

Example 100

A suspension of 2.04 g of 2- (4-chlorophenyl) -4-methyl- [1] benzopyrano [4,3c] pyrazol-3 (2H) -one (Example 91b) in 49 ml of ethanol was added at 0-5 ° C. with stirring, treated with 0.76 g of sodium borohydride in portions. The reaction mixture was stirred at this temperature for 15 minutes and then poured into ice-cold water. The pH of the mixture is adjusted to 4-5 with glacial acetic acid and the mixture is filtered. The filtered solid was washed with water, dried and recrystallized from methanol to give 2- (4-chlorophenyl) -4-methyl-1,4-dihydro- [l] benzopyrano [4,3-c] pyrazole 3 (2H). -on, m.p. 143-147 ° C.

Example 101

A mixture of 2.63 g of 2- (4-fluorophenyl) -4-methyl- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 37) and 67 ml of ethanol The mixture was treated with 0.67 g of sodium borohydride in portions at 5 ° C with stirring for 5 minutes. The reaction mixture was stirred at the above temperature for 0.5 hour and then added to a cooled mixture of water and petroleum ether (b.p. 62-68 ° C, 9: 1) with stirring. The pH of the reaction mixture was adjusted to 4-5 with glacial acetic acid and the resulting mixture was filtered. The filtered solid was washed and dried to give 2- (4-fluorophenyl) -4-methyl-1,4-dihydro- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one as its monohydrate, m.p. 114-117 ° C.

Example 102

a) 100 mg of ethyl [2- (4-chlorophenyl) -3-oxo-2,3-dihydro [l] benzopyrano [4,3-c] pyrazole-4-acetate] (Example 41); A mixture of 4-methoxybenzyl alcohol (32 ml) was heated at 150 ° C for 50 minutes with stirring. The mixture was then cooled to room temperature, diluted with ether and filtered to give (4-methoxybenzyl) -2- (4-chlorophenyl) -3-oxo-2,3-dihydro- [1] benzopyrano [4.3]. -c] pyrazole-4-acetate, m.p. 161-163 ° C.

b) 1.38 g of (4-methoxybenzyl) -2- (4-chlorophenyl) -3-oxo-2,3-dihydro- [l] benzopyrano [4,3-c] pyrazole-4-acetate and A mixture of dichloromethane (ml) was stirred at 0 ° C and 0.28 ml of methoxybenzene and 3.45 ml of trifluoroacetic acid were added. The reaction mixture was stirred at 0 ° C for 110 minutes and then filtered. The filtrate was diluted with ice-cold water and the resulting solid was filtered, washed with water and dried. The solid was stirred with ether (10 mL) for 5 min and filtered to give 2- (4-chlorophenyl) -3-oxo-2,3-dihydro- [l] benzopyrano [4,3-c] pyrazole-4-acetic acid having a melting point of 195-198 ° C.

Reference Example 103

A mixture of 2.0 g of 2- (4-chlorophenyl) -4-methyl- [l] benzopyrano [4,3c] pyrazol-3 (2H) -one (Example 91b) and 36 ml of propan-2-ol was stirred at room temperature. while being treated with 3.2 ml of 2M sodium hydroxide solution. The reaction mixture was stirred for 10 minutes, then poured into water and acidified with 5M hydrochloric acid. This mixture was extracted with dichloromethane and the combined extracts were washed with water. A solid formed which was filtered off and dried to give 1- (4-chlorophenyl) -4- {1- [2- (4-chlorophenyl) -3-hydroxy-2,4-dihydro- [1] benzopyrano [4,3c] Pyrazol-4-ylidenemethyl] ethylidene} -3- (2-hydroxyphenyl) 2-pyrazolin-5-one, m.p. 220-222 ° C.

Reference Example 104

Similarly to Example 103, 1.43 g of 2- (3,4-dichlorophenyl) -4-methyl- [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 36) and A mixture of propan-2-ol (5 ml) was treated with 2.1 ml of 2M sodium hydroxide solution with stirring for 15 minutes. The reaction mixture was acidified and the solid formed was filtered off and dried. The solid product was stirred in dichloromethane (10 mL) for 10 minutes and filtered to give 1- (3,4-dichlorophenyl) -4- {1- [2- (3,4-dichlorophenyl) -3-hydroxy] -2,4-dihydro- [1] benzopyrano [4,3-c] pyrazol-4-ylidenemethyl] ethylidene} -3- (2-hydroxyphenyl) 2-pyrazolin-5-one, m.p. 215'C.

Example 105

Similarly to Example 101, 2.12 g

4-Methyl-2- (4-methylphenyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one (Example 43) was treated with 0.56 g of sodium borohydride in 50 ml of ethanol. The product was recrystallized from industrial methylated alcohol to give 4-methyl-2- (4-methylphenyl) -1,4-dihydro- [l] -benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. 121 'C.

HU 208 977 Β

Example 106

Preparation of tablets

Tablets are prepared containing 100 parts by weight of active ingredient, 250 parts by weight of lactose, 22 parts by weight of corn starch, 10 parts by weight of polyvinylpyrrolidone and 3 parts by weight of magnesium stearate. The active ingredient, lactose and a portion of the starch are comminuted, blended and the resulting mixture granulated with an ethanolic solution of polyvinylpyrrolidone. The dry granulate is mixed with magnesium stearate and residual starch. The resulting mixture is compressed into a tablet machine containing tablets containing 100 mg of the active ingredient.

Claims (44)

PATENT CLAIMS A process for the preparation of a compound of formula (I): wherein: R, hydrogen or R _{2 is a} bond, R ₂ is a bond to one of R or R ₃ , R ₃ is a bond with one of R ₂ or R ₄ , R _{4 is} hydrogen or R _{3 is} bond, R _{5 is} hydrogen or methyl, R 8 is hydrogen, halogen, C 2 -C 6 alkanoyl, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, carbamoyl. or a carboxy group, or R ₅ and R 8 with the carbon atom to which they are attached are cyclopropyl, R _{7 is} hydrogen, halogen, trifluoromethyl, methoxy, C 1-6 alkyl, C 1-6 alkylthio or C 1-6 alkylsulfinyl, R _{8 is} hydrogen, halogen or trifluoromethyl, R ₉ and R _{10 are the} same or different and are each halogen or R _{9 is} hydrogen and R _{10 is} hydrogen, halogen, trifluoromethyl, hydroxy, nitro, C 2 -C 6 alkanoyloxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, with the proviso that when R 1 and R ₂ represent a bond and R ₃ and R _{4 are} also a bond and R ₈ , R ₇ , R ₈ , and R ₁₀ are each hydrogen and R ₉ is hydrogen or 8- R ₅ is other than hydrogen, characterized in that a) for the preparation of compounds of the formula I in which R 1 and R ₂ together represent a bond, and R ₃ and R ₄ together represent a bond, R ₅ , R ₆ , R 7, ^R 8> ^R 9 and R 10 are as defined herein, a compound of formula I wherein R 1 is hydrogen, R ₂ and R _{3 are taken} together to form a bond, R _{4 is} hydrogen and R ₅ , R ₆ , R ₇ , R _g , R ₉ and R _{10 are} as defined above, oxidized; b) for the preparation of compounds of the formula I in which R ₁ and R ₂ together represent a bond, R ₃ and R ₄ together also represent a bond and R ₅ , ^R 6 - 7> ^R 8> R 9 and R ₁₀ a compound of Formula IV wherein R ₇ , R ₈ , R ₉ and R _{10 are} as defined above, or a tautomer thereof with an orthoester Va or a thioorthoester Vb C 1 -C 4 alkyl or benzyl and R ₅ and R 8 are as defined above, or when R 8 is alkanoyl, 2,2,6-tri (C 1 -C 6 alkyl) -1H-1,3-diox5-ene- With 4-one, the same or different alkyl groups; c) for the preparation of compounds of the formula I in which R ₁ and R ₂ together represent a bond, R ₃ and R ₄ together also represent a bond and R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ a compound of Formula VI wherein R _{u is} hydrogen or a tautomer thereof, or R n is -COR ₁₃ (R _{13 is} hydrogen, C 1-4 alkyl or benzyl); R ₁₂ is -COCHR ₅ R 8 (R ₅ and R 8 are as defined above) and R ₇ , R ₈ , R ₉ and R _{10 are} as defined above, with a base; d) for compounds of formula (I) for the preparation of in which R, is hydrogen, R ₂ and R ₃ bond together, _R4 is hydrogen and _R5, Rg, _{R7, R8, R9} and _R10 tangible meanings as round, an (I) compound wherein R, and R ₂ bond together, R ₃ and R ₄ together can also represent a bond and _R5, Rg, _{R7, R8, R9} and _R10 are the as defined above, reduced; e) for the preparation of compounds of formula I wherein R 1 _is hydrogen, R ₂ and R _{3 are taken} together, R _{4 is} hydrogen and R ₅ , R ₈ , R ₇ , R ₈ , R ₉ and R ₁₀ are meanings as circle, a compound (VII) - wherein _R14 is C1-4 alkyl and _R5, Rg, _R9 and _R10 are as defined above - with a compound of formula (VIII) - wherein R ₇ and R _And (i) optionally deacylating a compound of formula (I) wherein R _{10 is C} 1-6 alkoxy to form a compound of formula (I) wherein R _{10 is} hydroxy, (ii) optionally acylating a compound of formula (I) wherein R _{10 is} hydroxy to a compound of formula (I) wherein R _{10 is C} 2 -C 6 alkanoyloxy; compound of the formula, R and / or R ₇ C 1-6 alkylthio, (I) a compound of formula is oxidized wherein wherein R and / or substituted with R ₇ C 1-6 alkylsulfinyl group, (iv) of the desired formula ( The compound of formula I wherein R g is C 1 -C 6 alkylsulfinyl is oxidized to a compound of formula I wherein R g is C 1 -C 6 alkylsulfonyl; by hydrolysis and then decarboxylation to a compound of formula I wherein Rg is hydrogen, GB 208,977 Β (vi) optionally (I) a compound of formula wherein R ₆ C 2-6 alkoxycarbonyl group, a compound of formula (I) is hydrolyzed, wherein R ₆ COOH. (Priority: July 28, 1989) 2. A process according to claim 1 for the preparation of compounds of formula I wherein R _{5 is} hydrogen, R _{6 is} hydrogen, halogen, C 2 -C 6 alkanoyl, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl. thio, (C 1 -C 6) alkylsulfinyl, (C 1 -C 6) alkylsulfonyl, carbamoyl or carboxy or R ₅ and R _{6 with} the carbon atom to which they are attached represent cyclopropyl, R _{7 is} hydrogen, fluoro, chloro, trifluoro; methyl, C 1-6 alkylthio or C 1-6 alkylsulfinyl, R _{g is} hydrogen or chlorine and R ₉ and R ₁₀ are each fluorine or R _{9 is} hydrogen and R _{10 is} substituted at the 8 or 9 position of the benzene ring, and is hydrogen, fluoro, trifluoromethyl, hydroxy, nitro, C 2-6 alkanoyloxy or C 1-6 alkyl, or R ₁₀ is C 1-6 alkoxy at the 9-position of the benzene ring, kii reaction compounds. (Priority: July 28, 1989) A process for the preparation of a compound of formula (I) according to claim 1 or claim 2 wherein R g is hydrogen, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl or carboxy or R ₅ and R ₆ to which they are attached represent a cyclopropyl group, R _{7 is} hydrogen, fluoro, chloro, trifluoromethyl, C 1-6 alkylthio or 1- C 6 alkylsulfinyl, R _{g is} hydrogen or chlorine and R ₉ and R ₁₀ are each fluorine or R _{9 is} hydrogen and R ₁₀ is a benzene ring At the 8- or 9-position and represents hydrogen, fluoro, trifluoromethyl, hydroxy, nitro, (C 1 -C 6) -alkyl or R _{10 (C} 1 -C 6) -alkoxy in the 9-position of the benzene ring, compounds. (Priority: July 28, 1989) A process for the preparation of compounds of formula I according to claim 1 or 2, wherein R _{5 is} hydrogen, R _{6 is} hydrogen, halogen, C 2 -C 4 alkanoyl, C 2 -C 6 alkoxycarbonyl, C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, carbamoyl or carboxy, or R ₅ and R 8 with the carbon to which they are attached represent a cyclopropyl group, wherein starting compounds. (Priority: 8/28/1989) A process for the preparation of a compound of formula I according to claim 4 wherein R _{6 is} hydrogen, chlorine, bromine, acetyl, C 2 -C 4 alkoxycarbonyl, methylthio, ethylthio, methylsulfinyl. -, methylsulfonyl, carbamoyl, carboxy or R represents a cyclopropyl group, R ₅ and the carbon atoms to which they are attached, characterized in that corresponding starting compounds. (Priority: July 28, 1989) 6. Process for the preparation of compounds of formula I according to any one of claims 1 to 3, wherein R g is hydrogen, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or methylthio, characterized in that the appropriate starting compounds are reacted. (Priority: July 28, 1989) 7. A process according to any one of claims 1 to 6 for the preparation of compounds of formula I wherein R g is hydrogen or poroxycarbonyl, wherein the appropriate starting compounds are reacted. (Priority: July 28, 1989) 8. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3 wherein R g is hydrogen, characterized in that the appropriate starting compounds are reacted. (Priority: July 28, 1989) 9. A process for the preparation of a compound of formula I as claimed in any one of claims 1 to ₆ wherein R _{7 is} hydrogen, fluoro, chloro, trifluoromethyl, C 1-4 alkylthio or C 1-4 alkylsulfinyl, wherein starting compounds. (Priority: July 28, 1989) 10. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3 wherein R _{7 is} hydrogen, fluoro, chloro, trifluoromethyl, methylthio or methylsulfinyl, wherein the appropriate starting compounds are reacted. (Priority: July 28, 1989) 11. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 6, wherein R _{7 is a} fluorine atom, a chlorine atom, a trifluoromethyl or a methylthio group, characterized in that the appropriate starting compounds are reacted. (Priority: July 28, 1989) 12. Process for the preparation of compounds of formula I according to any one of claims 1 to 3, wherein R _{7 is a} fluorine atom or a chlorine atom, characterized in that the appropriate starting compounds are reacted. (Priority: July 28, 1989) 13. A process according to any one of claims 1 to 6 for the preparation of compounds of formula I wherein R _{8 is} hydrogen or chlorine, wherein the appropriate starting compounds are reacted. (Priority: July 28, 1989) 14. The method of claim 1, 2 or 4-13. A process according to any one of claims 1 to 6 which is a compound of formula (I) GB 208,977 Β thereof, wherein R is hydrogen and R _I0 hydrogen, fluoro, hydroxy, nitro, C 2-6 alkanoyloxy or C 1-4 alkoxy, characterized by reacting the corresponding starting compounds. (Priority: July 28, 1989) 15. A process according to claim 14 for the preparation of compounds of formula I wherein R _{10 is} hydrogen, fluoro, hydroxy, C 2 -C 4 alkanoyloxy or C 1 -C 4 alkoxy, characterized in that appropriate starting compounds are present. with. (Priority: July 28, 1989) 16. A process according to claim 15 for the preparation of compounds of formula I wherein R _{10 is} hydrogen or fluoro or C 2 -C 4 alkanoyloxy at the 8-position of the benzene ring or hydroxy or C 1 -C 4 alkoxy at the benzene ring. ring at the 9-position of the ring, characterized in that appropriate starting compounds are reacted. (Priority: July 28, 1989) 17. Process for the preparation of compounds of formula I according to any one of claims 1 to 3, wherein R _{9 is} hydrogen and R _{10 is} hydrogen or 8-fluorine, characterized in that the appropriate starting compounds are reacted. (Priority: July 28, 1989) A process for the preparation of a compound of formula (II) according to claim 1 wherein R _{5 is} hydrogen, R _{6 is} hydrogen, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or methylthio, R _{7 is} fluorine, a chlorine atom, a bromine atom, a trifluoromethyl or methylthio group, a R ₈ hydrogen atom or a chlorine atom, a R ₉ hydrogen atom, a R ₁₀ hydrogen atom, an 8-fluorine atom, an 8-propionyloxy, 9-hydroxy or 9-ethoxy group, starting compounds. (Priority: July 28, 1989) A process for the preparation of a compound of formula (III) according to claim 1 wherein R ₅ and R _{6 are} hydrogen, R _{7 is} hydrogen or chlorine, R _{8 is} hydrogen or chlorine, and R and R ₁₀ are each hydrogen. and reacting the appropriate starting compounds. (Priority: July 28, 1989) The process according to claim 1, wherein the compound is 2- (4-chlorophenyl) -4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, ethyl 2- (4- chlorophenyl) -3-oxo-2,3-dihydro- [1] benzopyrano [4,3-c] pyrazole-4-acetate, propyl 2- (4-chlorophenyl) -3-oxo-2 , 3-dihydro- [1H-benzopyrano [4,3-c] pyrazole-4-acetate, isopropyl-2- (4-chlorophenyl) -3-oxo-2,3-dihydro- [1] benzopyrano [4, 3-c] pyrazole-4-acetate, which comprises reacting the appropriate starting compounds. (Priority: July 28, 1989) 21. A process for the preparation of an immunomodulatory pharmaceutical composition comprising the compounds of formula (I) as an active ingredient. The active ingredient of any one of claims 1 to 6 is processed into a pharmaceutical composition together with the usual carriers, diluents, fillers and / or other excipients of the pharmaceutical compositions. (Priority: July 28, 1989) 22. The method of claim 21, wherein the pharmaceutical compositions are in unit dosage form. (Priority: 8/28/1989) 23. A process for the preparation of compounds of formula (I): wherein R 1 is hydrogen or together with R _{2 is a} bond, R ₂ is a bond with one of R ₁ or R ₃ , R ₃ is a bond to one of R ₂ or R ₄ , R _{4 is} hydrogen, or R _{3 is} bond, R _{5 is} hydrogen, or methyl, R _{6 is} hydrogen, halogen, C 2 -C 6 alkanoyl, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, carbamoyl - either a carboxy group or R ₅ and R _{6 with} the carbon atom to which they are attached represent a cyclopropyl group, R _{7 is} hydrogen, halogen, trifluoromethyl, methoxy, C 1-6 alkyl, C 1-6 alkylthio or C 1-6 alkylsulfinyl, R _{8 is} hydrogen, halogen or trifluoromethyl, R ₉ and R _{10 are the} same or different and are each halogen or R _{9 is} hydrogen and R _{10 is} hydrogen, halogen, trifluoromethyl, hydroxy, nitro, acetyloxy, C 1-6 alkyl or C 1-6 alkoxy, with the proviso that when R 1 and R ₂ represent a bond and R ₃ and R ₄ also represent a bond and R ₆ , R ₇ , R ₈ and R ₁₀ are each hydrogen and R ₉ is hydrogen or 8-methyl, then R ₅ is hydrogen different - characterized in that a) for the preparation of compounds of the formula I in which R ₁ and R _{2 are taken} together and R ₃ and R _{4 are taken} together, R ₅ , R ₆ , R ₇ , R _g , R 8 and R ₁₀ is intended to mean a compound of formula I wherein R 1 is hydrogen, R ₂ and R _{3 are taken} together, R _{4 is} hydrogen and R _{5 is} R ₈ , R ₇ , R ₈ , R ₉ and R _{10 are} as defined above. are oxidized; b) for the preparation of compounds of the formula I in which R ₁ and R ₂ together represent a bond, R ₃ and R ₄ together also represent a bond and R ₅ , R 8, R ₇ , R 8, R 9 and R ₁₀ or a tautomer thereof with an orthoester of formula Va or a thioorthoester of formula Vb wherein Y 1 is a compound of formula (TV): wherein R ₇ , R ₈ , R ₉ and R _{10 are} as defined above; C 4 -C 4 alkyl or benzyl and R ₅ and R 4 are as defined above, c) for the preparation of compounds of the formula I in which R ₁ and R ₂ together represent a bond, R ₃ and R ₄ together also represent a bond and R ₅ R ₆ , R ₇ , R _g , R ₉ and R ₁₀ meaning by subject matter, A compound of Formula VI wherein R _{n is} hydrogen or a tautomer thereof, or wherein R _n is -COR ₁₃ (R _{13 is} hydrogen, C 1-4 alkyl, or benzyl); ₁₂ is reacted with a base of the formula -COCHR 1 R 9 (R ₅ and R 8 are as defined above) and R ₇ , R ₈ , R ₉ and R _{10 are} as defined above; d) for the preparation of compounds of formula I wherein R 1 is hydrogen, R ₂ and R _{3 are taken} together, R _{4 is} hydrogen and R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ is a compound of formula I wherein R 1 is hydrogen; and R ₂ together represent a bond, R ₃ and R ₄ together represent a bond and R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , and R _{10 are} as defined above; e) for compounds of formula (I) for preparing, wherein R) is H, R ₂ and R ₃ bond together, _R4 is hydrogen and _{R5, R6, R7, R8, R9} and _R10 are the meanings according to the preamble circle, a compound of formula (VII): - wherein _R14 is C1-4 alkyl and _R5, Rg, _R9 and _R10 are as defined above - one (VIII) with a compound of the formula: - wherein R ₇ and R _{8 is} as defined above. (Priority: 08.08.1988) 24. A process according to claim 23 for the preparation of compounds of formula I wherein R _{5 is} hydrogen, R 8 is hydrogen, halogen, C 2 -C 6 alkanoyl, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl. thio, (C 1 -C 6) alkylsulfinyl, (C 1 -C 6) alkylsulfonyl, carbamoyl or carboxy or R ₅ and R _{6 on} the carbon atom to which they are attached represent cyclopropyl, R _{7 is} hydrogen, fluoro, chloro, trifluoro; methyl, C 1-6 alkylthio or C 1-6 alkylsulfinyl, R _{g is} hydrogen or chlorine and R ₉ and R ₁₀ are each fluorine or R _{9 is} hydrogen and R _{10 is} substituted at the 8 or 9 position of the benzene ring, and is hydrogen, fluoro, trifluoromethyl, hydroxy, nitro, acetyloxy, or C 1-6 alkyl, or R ₁₀ is C 1-6 alkoxy at the 9-position of the benzene ring, wherein reaction. (Priority: 08/09/1988) 25. A process according to claim 23 or 24 for the preparation of a compound of formula I wherein R g is hydrogen, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl or carboxy, or R ₅ and R ₆ to which the carbon to which they are attached are cyclopropyl, R _{7 is} hydrogen, fluoro, chloro, trifluoromethyl, C 1-6 -alkylthio or 1- C6 alkylsulfinyl, _R8 is hydrogen or chlorine and R ₉ and R ₁₀ each represent fluoro, or R ₉ is hydrogen and R, _o substituents on the benzene ring At the 8- or 9-position and represents hydrogen, fluoro, trifluoromethyl, hydroxy, nitro, (C 1 -C 6) -alkyl or R _{10 (C} 1 -C 6) -alkoxy in the 9-position of the benzene ring, compounds. (Priority: August 9, 1988) 26. A process according to claim 23 or 24 for the preparation of compounds of formula I wherein R _{5 is} hydrogen, R 8 is hydrogen, halogen, C 2 -C 4 alkanoyl, C 2 -C 6 alkoxycarbonyl, C 1-4 alkylthio, C 1-4 alkylsulfonyl, C 1-4 alkylsulfinyl, carbamoyl or carboxy, or R ₅ and R 8 with the carbon to which they are attached represent a cyclopropyl group, wherein compounds. (Priority 09/08/1988) 27. A process according to claim 26 for the preparation of compounds of formula I wherein R g is hydrogen, chlorine, bromine, acetyl, C 24 alkoxycarbonyl, methylthio, ethylthio, methylsulfinyl. , methylsulfonyl, carbamoyl, carboxy or R ₅ R groups and the carbon to which they are attached represent cyclopropyl, characterized by reacting the corresponding starting compounds. (Priority: 08/09/1988) 28. A 23-27. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3 wherein R g is hydrogen, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or methylthio, characterized in that the appropriate starting compounds are reacted. (Priority: August 9, 1988) 29. A 23-28. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, wherein Rg is a hydrogen atom or a propoxycarbonyl group, which comprises reacting the appropriate starting compounds. (Priority: August 9, 1988) 30. A 23-29. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3 wherein R g is hydrogen, characterized in that the appropriate starting compounds are reacted. (Priority 09/08/1988) 31. A 23-30. A process for the preparation of a compound of formula I as claimed in any one of claims 1 to ₆ wherein R _{7 is} hydrogen, fluoro, chloro, trifluoromethyl, C 1-4 alkylthio or C 1-4 alkylsulfinyl, wherein starting compounds. (Priority: August 9, 1988) 32. A 23-31. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3 wherein R _{7 is} hydrogen, fluoro, chloro, trifluoromethyl, methylthio or methylsulfinyl, wherein the appropriate starting compounds are reacted. (Priority: August 9, 1988) 33. A 23-32. A method according to any one of claims 1 to 22 A process for the preparation of compounds of formula I wherein R _{7 is} fluoro, chloro, trifluoromethyl or methylthio, characterized in that the appropriate starting compounds are reacted. (Priority: August 9, 1988) 34. A 23-33. Process for the preparation of compounds of formula I according to any one of claims 1 to 3, wherein R _{7 is a} fluorine atom or a chlorine atom, characterized in that the appropriate starting compounds are reacted. (Priority: 08.08.1988) 35. A 23-34. Process for the preparation of compounds of formula I according to any one of claims 1 to 3, wherein R _{8 is} hydrogen or chlorine, characterized in that appropriate starting compounds are reacted. (Priority: August 9, 1988) 36. The method of claim 23, 24 or 26-35. Process for the preparation of compounds of formula I according to any one of claims 1 to 3, wherein R _{9 is} hydrogen and R 10 is hydrogen, fluoro, hydroxy, nitro, acetyloxy or C 1-4 alkoxy, characterized in that the corresponding starting compounds are reacted. . (Priority: August 9, 1988) 37. A process according to claim 36 for the preparation of compounds of formula I wherein R _{10 is} hydrogen, fluoro, hydroxy, acetyloxy, or C 1-4 alkoxy, which comprises reacting appropriate starting materials. (Priority: August 9, 1988) 38. A process according to claim 37 for the preparation of compounds of formula I wherein R10 is hydrogen or fluoro or acetyloxy at the 8-position of the benzene ring or hydroxy or C1-C4 alkoxy at the benzene ring. 9, wherein the appropriate starting compounds are reacted. (Priority: August 9, 1988) 39. A 23-38. Process for the preparation of compounds of formula I according to any one of claims 1 to 3, wherein R _{9 is} hydrogen and R _{10 is} hydrogen or 8-fluorine, characterized in that the appropriate starting compounds are reacted. (Priority: August 9, 1988) 40. The method of claim 23 for the preparation of compounds of formula (II) wherein _R5 is hydrogen, _R6 is hydrogen, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, or methylthio, R ₇ fluorine atom, a chlorine atom, bromine atom, trifluoromethyl or methylthio group, R ₈ hydrogen atom or chlorine atom R ₉ hydrogen atom, R ₁₀ hydrogen atom, 8-fluorine atom, 9-hydroxy or 9-ethoxy group, characterized in that appropriate starting compounds are reacted. (Priority: August 9, 1988) 41. The method of claim 23 for the preparation of compounds of formula (III) where R ₅ and R ₆ represents a hydrogen atom, R ₇ is hydrogen or chloro, R ₈ is hydrogen or chlorine and R ₉ and R ₁₀ are each hydrogen, wherein to react the appropriate starting compounds. (Priority: August 9, 1988) 42. The process of claim 23, wherein 2- (4-chlorophenyl) -4-methyl- [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, ethyl [2- (4) -chlorophenyl) -3-oxo-2,3-dihydro- [1] benzopyrano [4,3-c] pyrazole-4-acetate], propyl [2- (4-chlorophenyl) -3- oxo-2,3-dihydro- [1] benzopyrano [4,3-c] pyrazole-4-acetate], isopropyl- [2- (4-chlorophenyl) -3-oxo-2,3-dihydro- [l] benzopyrano [4,3-c] pyrazole-4-acetate], which comprises reacting appropriate starting materials. (Priority: 08.08.1988) 43. A process for the preparation of an immunomodulatory pharmaceutical composition comprising the compounds of formula (I) as an active ingredient, wherein the active ingredient of any one of claims 23-42 is formulated together with the customary carrier, diluent, excipient and / or other excipients. (Priority 09/08/1988) 44. The method of claim 43, wherein the pharmaceutical compositions are in unit dosage form.